Tehran immediately linked the attack in Iran's restive southeastern Sistan and Baluchistan province to an ongoing U.S.-led conference in Warsaw largely focused on Iran, just two days after the nation marked the 40th anniversary of its 1979 Islamic Revolution.
The bombing also raised the specter of possible Iranian retaliation targeting a Sunni militant group called Jaish al-Adl that claimed the attack, which largely operates across the border in nuclear-armed Pakistan. Recent militant assaults inside Iran have sparked retaliatory ballistic missile strikes in Iraq and Syria.
The bombing Wednesday night struck the bus traveling on a road between the cities of Khash and Zahedan, a mountainous region along the Pakistani border that is also near Afghanistan. Images after the blast published by semi-official news agencies showed the explosion tore the bus apart, as passers-by used the light of their cellphones to illuminate the debris.
The state-run IRNA news agency, citing what it described as an "informed source," offered initial casualty figures of 20 dead and 20 wounded. The Revolutionary Guard later reported on its website that 27 were killed and 13 wounded.
The Guard, which answers only to Iran's Supreme Leader Ayatollah Ali Khamenei, issued a statement saying a vehicle loaded with explosives targeted a bus carrying border guards affiliated with its force.
Sistan and Baluchistan province, which lies on a major opium trafficking route, has seen occasional clashes between Iranian forces and Baluch separatists, as well as drug traffickers.
However, in recent months, there's been an uptick in assaults by the Sunni extremist group Jaish al-Adl, or the "Army of Justice." Since its founding in 2012, it has abducted or killed border guards in hit-and-run assaults from its havens in Pakistan. It kidnapped 11 Iranian border guards in October. Five later were returned to Iran and six remained held.
Jaish al-Adl claimed Wednesday's bombing in a statement online. Iranian state-run and semi-official media also blamed the group for the attack.
While Iran has been enmeshed in the wars engulfing Syria and neighboring Iraq, it largely has avoided the bloodshed plaguing the region. However, attacks have happened.
In 2009, more than 40 people, including six Guard commanders, were killed in a suicide attack by Sunni extremists in Sistan and Baluchistan province. Jundallah, a Sunni extremist group whose members have joined Jaish al-Adl, claimed responsibility for that attack.
In the case of Jundallah, Pakistan assisted Iran in apprehending its leader, whom Tehran executed in 2010. Iran has sought the cooperation of Pakistan in recent cases involving Jaish al-Adl as well.
However, a bombing like this inside of Iran likely will draw an immediate reaction from the Guard, a massive paramilitary organization that both controls Iran's ballistic missile program and vast chunks of its economy.
Iran fired ballistic missiles into Syria over a bloody Islamic State attack on Tehran targeting parliament and the shrine of Ayatollah Ruhollah Khomeini in 2017 that killed at least 18 people. In September, Iran fired missiles into Iraq targeting a base of an Iranian Kurdish separatist group after an attack on a border post.
The Revolutionary Guard also launched six ballistic missiles as well as drone bombers in October toward eastern Syria, targeting militants it blamed for an attack on a military parade that killed at least 24 people.
Iran increasingly has blamed the militant attacks targeting it on Saudi Arabia and the United Arab Emirates. Saudi Crown Prince Mohammed bin Salman for instance in a 2017 interview suggested the kingdom knew it was a "main target of Iran."
"We are not waiting until there becomes a battle in Saudi Arabia, so we will work so that it becomes a battle for them in Iran and not in Saudi Arabia," he said then. Prince Mohammed is due in Pakistan, a major recepient of the kingdom's largess, in the coming days.
The U.S.-led conference in Warsaw is the work of President Donald Trump, who campaigned on a promise of tearing up Tehran's nuclear deal with world powers. Trump withdrew the U.S. from the accord last May. Since then, the United Nations says Iran has kept up its side of the bargain, though Iranian officials have increasingly threatened to resume higher enrichment.
Amid the new tensions, Iran's already-weakened economy has been further challenged. There have been sporadic protests in the country as well, incidents applauded by Trump amid Washington's maximalist approach to Tehran.
Iran's Foreign Minister Mohammad Javad Zarif directly linked the meeting to the attack Wednesday.
"Is it no coincidence that Iran is hit by terror on the very day that (hashtag)WarsawCircus begins?" Zarif wrote on Twitter. "Especially when cohorts of same terrorists cheer it from Warsaw streets & support it with (Twitter) bots?"
Khamenei, who earlier approved President Hassan Rouhani's outreach to the West during the nuclear deal negotiations, dismissed any future dealings with the U.S.
"About the United States, the resolution of any issues is not imaginable and negotiations with it will bring nothing but material and spiritual harm," Khamenei said in a statement.
Zarif earlier predicted the Warsaw summit would not be productive for the U.S.
"I believe it's dead on arrival or dead before arrival," he said at a news conference before the bombing.