NATO launched its biggest offensive in Afghanistan since the 2001 war, targeting the Taliban and drug lords as hundreds of people rallied in the east against US soldiers killing civilians.
Operation Achilles, which will eventually involve 4,500 NATO soldiers and 1,000 Afghans, began about dawn in Helmand province - the opium centre of the world's biggest producer, the head of the alliance's southern command Dutch Major-General Ton van Loon said in a statement.
The Taliban over-ran the key Helmand town of Musa Qala a month ago, ending a controversial truce, but a NATO spokeswoman said Achilles was not specifically aimed at regaining the town.
"It signifies the beginning of a planned offensive to bring security to northern Helmand and set the conditions for meaningful development that will fundamentally improve the quality of life for Afghans in the area," van Loon said.
NATO has about 33,000 troops in the country, including support personnel.
The open-ended operation is aimed largely at allowing the repair and expansion of the province's Kajaki dam hydroelectric facility.
"Operations will focus on improving security in areas where Taliban extremists, narco-traffickers and other elements are trying to destabilise the government," van Loon said.
More than 4,000 people died in fighting last year, the bloodiest since US-led forces ousted the Taliban in 2001.
NATO, the US and the Taliban are warning of a bloody spring offensive as the snows melt, with both sides vowing to take the initiative.
The offensive came as hundreds of people protested in the eastern city of Jalalabad, near Pakistan, over the killing of several civilians by US troops on Sunday.
At least 2,000 people blocked the highway between the city and Kabul, a major trade route to Pakistan, chanting "Death to Americans!", witnesses said.
They demanded strict action by the government against the Marines responsible, who opened fire after their convoy was hit by a suicide bomber.
Officials say at least 10 civilians were killed and the New York-based Human Rights Watch says between eight and 16 died.
The US military will only say 16 people died in the suicide attack and subsequent shooting after militants opened fire.
"Suicide bombers in Afghanistan regularly pose as civilians, but that doesn't give coalition forces carte blanche to respond with indiscriminate fire," Human Rights Watch's Asia director, Brad Adams said in a statement.
"The fact that the insurgents violate the laws of war doesn't absolve the US and its allies of the need to observe them.
Human Rights Watch said it was "concerned that the US military is attempting to control information" about the incident, saying the military confiscated the cameras of local and foreign journalists and deleted images and footage.
The Afghan government has launched an inquiry, but previous such investigations by the government, NATO and US forces have done nothing more than confirm initial witness accounts.
US forces also killed nine civilians - five women, three children and an old man - with a 2,000 pound bomb near Kabul after a post was attacked.
"The US military should ensure that meaningful investigations take place in both cases," Human Rights Watch said.
"Appropriate action, including disciplinary measures and prosecution, should be undertaken as warranted."
Analysts say civilian deaths undermine support for foreign troops in a country where most of the population is seeing almost no reconstruction and development to lift living standards.
Afghan leaders say foreign soldiers need to work more closely with local soldiers and police to be able to tell militants from ordinary people and minimise civilian deaths.