To investigate the effect of slow-release (SR) clarithromycin on colonization and the development of resistance in oropharyngeal and nasal flora, a double-blind, randomized, placebo-controlled trial was performed with 8 weeks of follow-up. A total of 296 patients with documented coronary artery disease were randomized in the preoperative outpatient clinic to receive a daily dose of SR clarithromycin (500 mg) (CL group) or placebo tablets (PB group) until the day of surgery. Nose and throat swabs were taken before the start of therapy, directly after the end of therapy, and 8 weeks later. The presence of potential pathogenic bacteria was determined, and if they were isolated, MIC testing was performed. Quantitative culture on media with and without macrolides was performed for the indigenous oropharyngeal flora. In addition, analysis of the mechanism of resistance was performed with the macrolide-resistant indigenous flora. Basic patient characteristics were comparable in the two treatment groups. The average number of tablets taken was 15 (standard deviation = 6.4). From the throat swabs, Haemophilus parainfluenzae was isolated and carriage was not affected in either of the treatment groups. Nasal carriage of Staphylococcus aureus, however, was significantly reduced in the CL group (from 35.3 to 4.3%) compared to the PB group (from 32.4 to 30.3%) (P < 0.0001; relative risk [RR], 7.0; 95% confidence interval [CI], 3.1 to 16.0). Resistance to clarithromycin was present significantly more frequently in H. parainfluenzae in the CL group after treatment (P = 0.007; RR, 1.6; 95% CI, 1.1 to 2.3); also, the percentage of patients with resistance to macrolides in the indigenous flora after treatment was significantly higher in the CL group (31 to 69%) (P < 0.0001; RR, 1.9; 95% CI, 1.4 to 2.5). This persisted for at least 8 weeks. This study shows that besides the effective elimination of nasal carriage of S. aureus, treatment with SR clarithromycin for approximately 2 weeks has a marked and sustained effect on the development of resistance in the oropharyngeal flora for at least 8 weeks.