It's a wildly popular antibiotic used to treat bronchitis and other common bacterial infections in just a few days.
"They found a slight increase in deaths from sudden cardiac failure, sudden heart failure. And that's worrisome," said ABC News Chief Medical Editor Dr. Richard Besser.
The study from Vanderbilt University looked at more than a half-million patients from 1992 to 2006.
Researchers found that patients on Zithromax who were prone to heart problems were two and a half times more likely to die from cardiovascular causes while taking the medication. That's versus patients who were on another antibiotic, amoxicillin.
"The risk of dying from taking a course of azithromycin was 45 in a million," said Besser. "The chances of dying crossing the street are greater than from taking this antibiotic."
The lead author of the study said he believes doctors prescribe Zithromax over amoxicillin because it's easier to take. And it's extremely popular: Last year doctors wrote 55.3 million prescriptions for Zithromax, with sales last year totaling $464 million.
Some doctors are urging caution about this new study, noting that patients taking Zithromax shouldn't panic.
"Physicians and patients, particularly if they have heart disease, should be cautious about taking Zithromax," said Dr. Steven Nissen, a cardiovascular specialist at the Cleveland Clinic.
Azithromycin is marketed by Pfizer. The drug company said in a statement, "Patient safety is of the utmost importance," and that the company would review the new study.