The bomb planted on the road in Birmal near Wana, the mean town of South Waziristan, targeted a vehicle carrying Taliban commander Ghulam Jan who provided shelter to Uzbek fighters in the area.
An official of political office of the South Waziristan agency said that Jan was the target of the attack.
"He was killed along with one of his cousins and three bodyguards who were travelling with him," said the official on anonymity as he was not allowed to talk to media.
It was not clear who was behind the attack but Jan had enmity with Mullah Nazir group that controls Wana and adjacent areas, because he had opposed expulsion of Uzbeks from South Waziristan by Nazir in 2007.
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He was later banished from the district but had patched up with the group's new leadership sometimes ago after Nazir was killed last year and was allowed to return through an agreement.
Several small militant groups are active in the region, quick to shift their alliances and also fight with each other often.
Pakistan launched a major operation in South Waziristan in 2010 and claimed victory against the militants after several weeks of fighting.