In a study published online by the British medical journal The BMJ, the team said clarithromycin use was associated with a 76-percent higher risk of cardiac death, compared to use of penicillin V.
"The absolute risk difference was 37 cardiac deaths per 1 million courses with clarithromycin," reported the trio from the Statens Serum Institute's epidemiology department in Copenhagen.
The risk stopped when treatment ended.
Clarithromycin is prescribed to millions of people every year, to treat bacterial infections like pneumonia, bronchitis and some skin infections.
The team had analysed data from more than five million antibiotics courses given to Danish adults aged 40 to 74 in the period 1997 to 2011.
Of the patients, just over 160,000 had received clarithromycin, 590,000 roxithromycin, and 4.4 million penicillin V.
Clarithromycin and roxithromycin are macrolides -- antibiotics that affect the electrical activity of the heart muscle and are thought to increase the risk of fatal heart rhythm problems, the researchers said.
No increased in risk was observed with roxithromycin.
While the absolute increase in risk with clarithromycin was small, the team said, it was "one of the more commonly used antibiotics in many countries... thus the total number of excess cardiac deaths may not be negligible".
The researchers called for their findings to be confirmed in further studies, even as a host of other experts pointed out that the study did not warrant a halt to clarithromycin use.
There were shortcomings in the paper, including that the researchers had no data on whether patients smoked or were obese -- which could explain some of the differences in death rates, said Kevin McConway, an applied statistics professor at The Open University.
"Since in any case the cardiac death rate while on these drugs is very small, this isn't a risk that I personally would worry about anyway," he wrote in a reaction distributed by the Science Media Centre.
Mike Knapton of the British Heart Foundation said it was already known that doctors should exercise caution when prescribing clarithromycin to patients with a certain heart syndrome.
"The bottom line is no one should be taking antibiotics unless they absolutely have to and doctors should give careful consideration before prescribing them," he said.