Epidemics of community-acquired pneumonia (CAP) are a frequent cause of morbidity among Russian military trainees. We evaluated azithromycin prophylaxis against CAP. In 2001-2002, incoming military trainees were randomized to 1 of 3 trial arms by training group: azithromycin, 500 mg per week for 8 weeks (R1); azithromycin, 1500 mg once at enrollment (R2); or no therapy (R3). During the 22 weeks of training, CAP was diagnosed in 20.2% of 678 subjects in the R3 group, 8.6% of 508 subjects in the R1 group, and 10.3% of 507 subjects in the R2 group. Throat carriage cultures revealed that the proportion of Streptococcus pneumoniae isolates with resistance to macrolides correspondingly increased during the study, from 0% (all) to 40% (R1) and 22.6% (R2) by week 20. Azithromycin prophylaxis is effective against CAP in a healthy population of young men at transient high risk of disease; however, azithromycin use must be tempered with the possible concomitant risk of selection for resistant endemic pathogens.