Drug czar, General Teodoro Campo, the commander of the country's US-backed police force, has been rocked by corruption scandals amid an anti-corruption shake-up.
Four other top generals of the National Police, which has been a principal beneficiary of more than $2 billion in US military aid in recent years, were removed from their posts.
"The message the president wants to send is that he is not going to tolerate corruption in any state institution," a senior government spokesman said.
President Alvaro Uribe, a strong supporter of Washington's war on drugs, accepted the resignation of General Campo as head of the police force.
Marta Lucia Ramirez with military
officers in Bogota before she quit
General Jorge Daniel Castro, the former police commander of the capital Bogota, will now take over the hotseat, government spokesman Ricardo Galan said.
The shake-up comes after Colombia's Defence Minister Marta Lucia Ramirez, who oversaw a military buildup against leftist rebels, resigned on Sunday.
Her departure followed mounting pressure from top generals angry at her management style and efforts to root out corruption.
With about 100,000 officers, the National Police has been deeply shaken by a wave of embarrassing corruption cases, drawing concern from key ally ,the United States.
Earlier this year, the government sacked an army general and a regional police commander amid allegations their officers took $1 million in bribes to return two tons of cocaine seized last year.
Happier days for Colombia's Uribe
and general Teodoro Campo
Last year, dozens of senior police officers, including a former president's security coordinator, were investigated after about $2 million of US money disappeared.
Colombia is the world's largest producer of cocaine and the United States consumes more of the drug than any other nation.
Uribe took office in August 2002 on pledges to crack down on drug trafficking fuelling a four-decade guerrilla war.