Ahead of his first meeting with President Barack Obama here Wednesday, Sharif said he wants to see US-Pakistan relations improve "but the issue of drones has become a major irritant in our bilateral relationship".
"The use of drones is not only a continual violation of our territorial integrity but also detrimental to our resolve and efforts at eliminating terrorism from our country," he said in an address Tuesday at the US Institute of Peace in Washington.
His comments came as Amnesty International and Human Rights Watch issued reports Tuesday detailing civilian casualties from US drone strikes and called for more transparency from the Obama administration.
The Amnesty report even suggested the US "appears to have committed very serious" human rights violations that might even amount to war crimes.
But White House Spokesman Jay Carney said the US strongly disagrees with claims that the drone strikes violate international law.
"US counterterrorism operations are precise, they are lawful, and they are effective, and the United States does not take lethal strikes when we or our partners have the ability to capture individual terrorists," he said.
The US takes "extraordinary care" to avoid the loss of civilian lives, Carney said, but there's "risk that exists in every war" that civilians will be harmed.
He also said that the estimates made by outside groups of the number of civilian casualties are much higher than the US government's totals, calling the difference in totals a "wide gap."
In a preview of the Obama-Sharif meeting, Daniel Markey, a senior fellow at the Council on Foreign Relations, said the US and Pakistan are not in alignment over which groups are targeted by drones.
"Both of them are willing to go after Al Qaeda core leadership to some extent and both of them are certainly willing to go after Pakistani Taliban," he said.
"There has been difference of opinion on Afghan Taliban and in particular [the] Haqqani network which the US has seen as being affiliated with Al Qaeda, has been wanting to target and has been targeting with drones."
But Pakistan sees it "as being less of a threat and certainly not a direct threat to Pakistani civilians or the Pakistani state."