Chlamydia pneumoniae has been associated with cardiovascular diseases, and C. pneumoniae infection is treatable with macrolides. In this comparative cohort study, 634 users of macrolides and 3827 users of penicillins were identified from the Danish Health Service Registry of Prescriptions and followed up for an average of 6 months. The patients were then linked to the Regional Hospital Discharge Registry to assess the outcome of hospitalization for cardiovascular disease. In the first 3 months, the relative risk (RR) of admission for a cardiovascular disease was 0.48 (95% confidence interval, 0.27-0.88) in users of macrolides compared with users of penicillins. No difference was seen after 3 months. Interaction analyses indicated that the lower risk seen in users of macrolides could be more pronounced in patients without versus those with a previous cardiovascular disease (RR, 0.39 vs. 0.52), in patients >or=60 versus <60 years old (RR, 0.39 vs. 0.64), and in men versus women (RR, 0.35 vs. 0.67).