BACKGROUND: In resource-poor settings, control of Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) among female sex workers (FSWs) is difficult. We sought to determine whether periodical antibiotic treatment (PAT) might be effective in controlling these infections among West African FSWs. Secondary objectives were to determine the impact of PAT on human immunodeficiency virus (HIV) incidence among FSWs and on NG/CT prevalence among their clients. METHODS: Cluster-randomized, double-blind, placebo-controlled trial among FSW communities in Benin and Ghana. Within each of 9 pairs of clusters of FSW communities, one was allocated to receive, during 9 months, a monthly antibiotic (alternatively ciprofloxacin or azithromycin, n = 296 FSWs) and the other a placebo (n = 340 FSWs). Prevalence of NG/CT infections was measured at 3-month intervals using the polymerase chain reaction. HIV status was determined at the beginning and at the end of the study. RESULTS: After adjusting for age, HIV status, duration of prostitution, price per intercourse and condom use, and accounting for prevalence at enrollment and cluster-pairing effect, prevalence ratios (intervention vs. placebo) of NG infection were 0.77 (P = NS), 1.07 (P = NS), and 0.49 (P = 0.05) at the first, second, and third follow-up visits, respectively. PAT neither reduced significantly CT prevalence or HIV incidence among FSWs nor NG/CT prevalence among their clients. CONCLUSION: The only beneficial impact of PAT was on the prevalence of gonococcal infections among FSWs 9 months after the beginning of the intervention. Although PAT could be more effective in other circumstances, for instance, in the early stages of a program for FSWs, it can not be recommended at present as a routine strategy to control cervical infections among FSWs.