Police yesterday identified the victim as John Mariani, 65, of New York, and said he was attacked on Friday night when his taxi was intercepted by gunmen in a car and on a motorcycle.
They said the assailants tried to take his wallet and personal belongings and shot him when he resisted. The attackers then fled.
Police offered a USD 16,000 reward for information leading to the arrest of the perpetrators.
The US Embassy had no immediate comment.
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El Poblado neighbourhood where the shooting happened is one of the Medellin's wealthiest and safest enclaves.
It is a leafy neighbourhood that is home to the city's vibrant dining scene and dozens of high-rise apartment buildings and hotels.
Medellin, the country's second biggest city, is a far cry from the 1980s when it was the headquarters for Pablo Escobar's feared Medellin cocaine cartel, and it has been experiencing a boom in tourism. The New York Times featured it at No. 11 on its list of 52 places to go in 2015.
Seven Colombians were extradited to the US last year to face charges in the stabbing death of a Drug Enforcement Administration agent, James "Terry" Watson, who was killed during a botched "express kidnapping" by a ring that targeted unsuspecting passengers hailing taxi cabs in Bogota.