The purpose of this double-blind study was to assess the effect of azithromycin and clarithromycin on oral and fecal microflora. Bacterial species from fecal samples and throat washes from healthy volunteers were identified and quantified before, during and after receipt of either placebo ( n=6), azithromycin (500 mg once daily for 3 days; n=6) or clarithromycin (500 mg twice daily for 7 days; n=6). In both antibiotic groups, the changes in oropharyngeal aerobic microflora following antibiotic administration were minor. Antibiotics neither changed the bacterial load of Streptococcus spp. compared with placebo, nor did macrolide-resistant streptococci emerge. In the fecal aerobic microflora, the number of organisms of the family Enterobacteriaceae decreased slightly after antibiotic administration in both the clarithromycin and the azithromycin groups, but levels normalized by day 21 after therapy. No colonization with nonfermenters or Clostridium difficile was seen, and the total number of anaerobic bacteria was not affected in any study group. In conclusion, there were no significant differences between azithromycin and clarithromycin in their effect on human oropharyngeal and intestinal microflora, nor was the use of these antibiotics associated with colonization by resistant, gram-positive organisms or overgrowth of opportunistic microorganisms.