Pakistan's president has warned the new head of US Central Command that missile strikes on Pakistani territory are "counter-productive".
President Asif Ali Zardari told General David Petraeus that such strikes were detrimental to the "war on terror".
Gen Petraeus also met Pakistan's army chief and prime minister during his first visit to the country since taking up his new position.
His responsibilities include Iraq and Afghanistan as well as Pakistan.
Correspondents say that this is the most high-profile protest yet from Islamabad against cross-border attacks by US forces based in Afghanistan.
"Continuing drone attacks on our territory, which result in loss of precious lives and property, are counter-productive and difficult to explain by a democratically-elected government," President Zardari said.
The US sees its strategic relationship with Pakistan as vital
"It is creating a credibility gap," the state-run Associated Press of Pakistan quoted him as saying.
Gen Petraeus' trip comes amid tensions between Islamabad and Washington over US missile strikes on suspected Islamist militants in north-west Pakistan.
"Pakistan has conveyed to the United States of America to respect its sovereignty and territorial integrity because the frequent drone attacks could lead to generate anti-America sentiments as well as create outrage and uproar among the people," the Pakistani defence ministry said in a statement.
Neither Gen Petraeus nor the US embassy in Pakistan made any immediate public comment in relation to the criticisms.
Gen Petraeus is being accompanied by US Assistant Secretary of State Richard Boucher.
Correspondents say the American envoys face the delicate task of explaining US actions without upsetting its ally.
They say that the fact the visit is taking place just days after Gen Petraeus took up his new post shows how important the US considers Pakistan's role to be in its "war on terror".
US commanders in Afghanistan strongly believe the answer to reducing violence in the country lies across the border in Pakistan's north-west.
The restive tribal area is considered a haven for al-Qaeda and Taleban-linked fighters.
But despite recent US missile strikes and the deployment of extra Pakistani troops to the region, militant attacks have continued.
More than 20 people were killed in two suspected US missile attacks in north-west Pakistan on Friday. But just two days later, eight Pakistani soldiers were killed in a suicide bomb attack on a security base near the border with Afghanistan.
Gen Petraeus has already commissioned a major review of US strategy in the region, which is expected to emphasise the need for a wider regional solution and more outreach to the Taleban.
Gen Petraeus was until recently commander of the US military in Iraq. He was widely credited with improving security there through the "surge" plan, which saw nearly 30,000 US troops deployed to trouble-spots.