Danish tourist Tomas Willemoes was shot and killed last week at close range by an unknown assailant in a popular plaza in the city's most upscale neighbourhood.
His murder came just days after an Israeli and Mexican, both of whom apparently were living in Medellin, were also killed.
Authorities are at a loss to explain the three killings, which came as the city was showcasing security gains to hundreds of business executives attending the World Economic Forum's annual meeting in Latin America.
"Any homicide is regretful, regardless of the reasons," Mayor Federico Gutierrez told journalists on Monday. "But it's very important to say that Medellin can't be a place for sex or drug tourism."
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Medellin's murder rate has fallen sharply since the 1980s, when the city was under siege by Pablo Escobar's army of killers. But it's ticking up again this year and authorities worry that it could spoil a nascent tourism boom.
Andres Munera, an independent travel guide in Medellin, shares the mayor's outrage and says he's had to turn away foreign customers who came to the city looking for drugs and prostitution.
He says the demand for such activities is strong and undercuts the efforts of residents who've worked hard to clean up their city's image as a haven for criminality.
Rare among many travel guides in Medellin, his company, Land Venture Travel, doesn't offer tours of the haunts made famous by Escobar's Medellin cartel before the fugitive capo's death at the hands of the police in 1993.
The area where Willemoes was shot last Thursday night, Parque Lleras, is home to the city's fanciest restaurants and bars.
"I'm sure this will have an impact," said Munera, referring to the murders. "The multiplier effect of bad press is always much higher than someone who tells their friends 'ah, what a great time I had in Medellin.