The government called the abduction a "dastardly terrorist act," but police said it was not clear whether Islamist militants, criminals seeking a ransom payment or members of a regional separatist group were responsible.
Gunmen seized John Solecki, head of the U.N. refugee office in the city of Quetta, as he traveled to work Monday morning, and shot and killed his driver, U.N. and Pakistani officials said.
Quetta is the capital of Baluchistan province, which partly borders Afghanistan. The U.N. High Commissioner for Refugees has worked for three decades in the region helping hundreds of thousands of Afghans fleeing violence in their homeland.
While a violent region, it has largely been spared the al Qaeda and Taliban insurgency wracking much of northwestern Pakistan, where several foreigners have been attacked or kidnapped in recent months.
In August, Lynne Tracy, the top U.S. diplomat in the northwest, in the same city.
"U.N. workers, including staff, diplomats, relief aides, and blue helmet peacekeepers, have been under fire more in the past few years than ever before - in Gaza, in Kosovo, in Baghdad, in Darfur and now in Pakistan - and the Secretary-General has begun to reevaluate the assignments or to suspend missions, given the higher danger levels of unarmed or lightly armed U.N. personnel," said CBS News foreign affairs analyst Pamela Falk from the U.N. Monday.
Senior police officer Khalid Masood said Solecki has worked in Quetta for more than two years. Ron Redmond, a UNHCR spokesman in Geneva, confirmed he is an American citizen.
At the scene of the kidnapping in an upscale neighborhood, a UNHCR Land Cruiser with at least one bullet hole was rammed against a wall.
Soon after the attack, authorities sealed exit routes from the city, officers said. Police also beefed up patrols and security checks along roads leading to Afghanistan, fearing Solecki may be taken there.
Quetta has been mentioned by Afghan officials as a likely hiding place for Mullah Omar and other Taliban leaders who are thought to have fled Afghanistan after the U.S. invasion in 2001.
Baluchistan is also the scene of a low-level insurgency driven by nationalist groups wanting more regional autonomy. They are not known to target foreigners.
General crime has also been on the rise in many parts of Pakistan, including kidnappings for ransom. An Iranian diplomat was abducted in Peshawar last year, and other foreigners and Afghans also have been taken.
The United Nations expressed "extreme shock and dismay" at the kidnapping and the killing of the driver.
"We strongly condemn this attack on humanitarian workers in Pakistan who have been doing their utmost to deliver their humanitarian mission," it said in a statement.
It was not clear whether the abduction would impact U.N. work in Pakistan. The bombing of Islamabad's Marriott hotel in September prompted new U.N. rules prohibiting expatriate staff from living with their children in cities including Quetta.
Solecki did not have a police escort while he was traveling, Masood said. "We have learned that he usually did not like to have an escort with him on his way to the office," he said.