State news agency Sana said Syrian rebels had driven a truck laden with over a tonne of explosives into a government checkpoint on a busy road.
The explosion appears to have set ablaze a nearby petrol tanker, increasing the damage and casualties.
According to Syrian Observatory for Human Rights, the al-Qaeda-linked al-Nusra Front carried out the attack.
“A man detonated a truck laden with explosives at a checkpoint near an agricultural vehicles company on the road linking Hama to Salamiya,” the Observatory said.
It said the attack had targeted government soldiers, but that most of the dead were civilians.
Pictures on Syria TV showed firemen battling to contain fires as black smoke rose from charred trucks and cars.
Hama saw some of the largest demonstrations against the rule of President Bashar al-Assad in the first months after the Syrian uprising began in March 2011.
But in late summer 2011, security forces stormed the city and have maintained control ever since.
Hama occupies a significant place in the history of modern Syria. In 1982, then-President Hafez al-Assad, father of Bashar, sent in troops to quell an uprising by the Sunni opposition Muslim Brotherhood. Tens of thousands were killed and the town flattened.
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