The CIA campaign had reportedly been suspended to avoid worsening relations between the United States and Pakistan after the deadly November 26 incident, which eroded even more the thin veneer of trust between the wary allies.
The four militants were killed late Tuesday when two missiles struck their compound on the outskirts of Miranshah in North Waziristan, a lawless tribal region near the Afghan border, security officials said.
The attack set the building on fire and flames could be seen from the roofs of houses in Miranshah, which lies five kilometers (three miles) away, according to residents.
It was the first missile strike in Pakistan since November 17. It remains to be seen if it presages a new round of attacks on Taliban and Al Qaeda-linked militants based in the remote territory bordering Afghanistan.
November's strike by NATO helicopters triggered outrage in Pakistan and aggravated tensions in an already shaky relationship with Washington, prompting Islamabad to block alliance supply convoys heading to Afghanistan.
Islamabad also ordered the United States last month to leave Shamsi air base in western Pakistan, from where it is believed to have launched some of its drones. Others are thought to be flown from within Afghanistan.
Pakistani defense analyst Talat Masood said the latest strike showed that the United States was pressing on with the covert campaign, as the lull had done little to mend frayed ties.
"America was exercising I think restraint over this period in order to improve its relationship with the Pakistan military and overall leadership," he said.
"Now that it has resumed, it shows that this policy of the US is not going to change," he said. "There has not been much movement in the US-Pakistan relationship and they cannot afford militants to become dangerous and effective by using this period to consolidate and gain strength."
A joint US-NATO investigation concluded last month that a catalog of errors and botched communications led to the soldier's deaths in November. But Pakistan rejected the findings, insisting the strikes had been deliberate.
NATO's probe said that both sides failed to give the other information about their operational plans or the location of troops and that there was inadequate coordination by US and Pakistani officers.
The US drone campaign has reportedly killed dozens of Al-Qaeda operatives and hundreds of low-ranking fighters in Pakistan since the first Predator strike in 2004.
But the program has incensed many Pakistanis and fuels widespread anti-American sentiment throughout the country.
The Los Angeles Times reported last month that the US Central Intelligence Agency had suspended drone strikes on gatherings of low-ranking militants in Pakistan due to the tensions caused by the campaign.
The latest drone strike came on the same day that a remote-controlled bomb killed 35 people and wounded more than 60 others in the troubled Khyber tribal region of northwest Pakistan.
The region had served as the main supply route for NATO forces operating in Afghanistan before the suspension triggered by the November incident.
There was no immediate claim of responsibility for the bombing but local residents suggested it was a tribal dispute.
The United States denounced the blast, which struck in a marketplace.
"We remain deeply committed to working with Pakistan to address these kinds of terrorist threats and the results of violent extremism," State Department spokeswoman Victoria Nuland said.
She added that Washington could not confirm reports that Al-Qaeda was behind the attack.
The border crossing for supplies to foreign troops fighting in Afghanistan remains closed. NATO said this month that it wants to get relations with Pakistan back on track as quickly as possible so it can be reopened.