The truck was passing through an area of Daraa province in southern Syria where troops loyal to President Bashar al-Assad are stationed when it was struck by the blast, the Syrian Observatory for Human Rights said.
"Twenty-one people were killed in the Nawa area (of Daraa), among them four children and six women, in a blast that detonated as their vehicle went past Tal al-Jumua," the Britain-based Observatory said.
A battalion of troops loyal to Assad "is positioned there, and is under siege by rebel forces", it added.
Daraa is the cradle of the uprising that broke out against Assad in March 2011.
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The Observatory says more than 115,000 people have been killed in the war that erupted after Assad's troops unleashed a brutal crackdown against protesters calling for political change.
Of those who have died, 41,533 were civilians, including 6,087 children and 4,079 women, according to the group.
Rebels fighting Assad's troops have made significant progress in recent months in Daraa, which is strategically located on the border with Jordan and near Damascus province.
A stalled peace initiative dubbed Geneva 2 has been proposed by Washington and Moscow aimed at bringing rebel and regime representatives to the negotiating table.
But the Syrian National Council (SNC), which is the biggest bloc within the Syrian opposition coalition, said at the weekend it would not join the talks planned for next month and would quit the umbrella group if it attends.
The SNC cited as its reasons for snubbing the talks the ongoing suffering of Syrians on the ground. It stressed it would not enter any negotiations before the fall of Assad's regime.
"There have been many ups and downs in this process. And that's not unexpected given how challenging the situation is on the ground," State Department spokeswoman Jen Psaki said.
"But we continue to press for the opposition to have a representative body at the Geneva conference, " she told reporters in Washington yesterday.