OBJECTIVE: To compare additional antibiotic usage for subjects randomized to Clari or Azi for the treatment of S. pyogenes pharyngitis/tonsillitis. METHOD: Subjects with symptoms of streptococcal pharyngitis/tonsillitis and S. pyogenes positive were enrolled in a randomized, multi-center, investigator blind, parallel comparative control study of 10 days Clari (250mg bid) versus 5 days Azi (250mg bid on day 1 then qd on days 2-5). Subjects were evaluated at the end of the treatment, at two weeks and at five weeks. Clinical and bacteriological evaluations as well as additional or concomitant antibiotics were evaluated at each visit. RESULTS: A total of 525 subjects aged 12 years and older were enrolled and randomized (Clari n=260; Azi n=265). The bacteriological eradication and clinical cure rates for Clari and Azi were 94% [195/207] vs 77% [155/202] (p<0.001) and 98% [200/205] vs 90% [182/202] (p<0.002), respectively, based on per-protocol analysis. A total of 445 subjects (Clari n=221; Azi n=224) were evaluable for the intent-to-treat analysis. There was a greater rate of additional antibiotic usage in the Azi group (12%, 26/224) compared to the Clari group (6%, 14/221). The total drug costs for additional antibiotics were $853 and $690 for the Azi and Clari groups, respectively. The major reason for additional antibiotics was due to bacteriological and clinical failures. CONCLUSIONS: Clari is superior to Azi in the eradication of S. pyogenes and in the resolution of symptoms of pharyngitis/tonsillitis. In addition, more subjects in the Azi group had additional antibiotics prescribed for pharyngitis/tonsillitis during the follow-up period. The lower rate of additional antibiotic usage would be expected to result in cost savings in the overall management of pharyngitis/tonsillitis.