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Summary Background Trachoma is the leading cause of preventable blindness. Pogrammes to prevent blindness due to trachoma are based on community-wide treatment with topical tetracycline. We assessed the potential of community-wide azithromycin treatment for trachoma control. Methods Pairs of villages in trachoma endemic areas of Egypt, The Gambia, and Tanzania were matched on trachoma rates in 1-10-year-old children, Villages were randomly assigned community-wide oral azithromycin treatment (three doses with intervals of 1 week) or treatment with 1% topical tetracycline (once daily for 6 weeks). Clinical examinations were done at baseline, 2-4.5 months, and 12-14 months after treatment Chhmydia tmchomatitis was identified by ligase chain reaction (LCR). Analyses were by intention to treat. Univariate comparisons and multivariate analyses were used to compare outcomes. Findings LCR positivity was correlated with clinical severity, but about 30% of Egyptian and Gambian villagers with no active disease were LCR positive, Village-wide LCR positivity ranged from 16-5% (Tanzania) to 43.6% (Egypt). Treatment compliance was over 90% except in the tetracycline treatment village in Egypt. Of the participants initially LCR positive, 866 (95%) of 924 who received at least one azithromycin dose and 482 (82%) of 587 who received 28 days or more topical tetracycline, were negative at follow-up. At 1 year, village-wide LCR positivity rates were substantially bwer than at baseline with both treatments; the decreases were greater with azithromycin than with tetracycline (93% us 77% in Egypt, 78 vs 66% in The Gambia, 64 vs 55% in Tanzania). Similarly, greater reduction in clinical activity occurred after azithromycin. In multivariate analyses, factors associated with being LCR positive at 1 year were: not receiving azithromycin; age under 10 years; and LCR positivity at baseline. Interpretation Community-wide treatment with oral azithromycin markedly reduces C tmchomatis infection and clinical trachoma in endemic areas and maybe an important approach to control of trachoma.