Persistent otitis media with effusion (POME) is found in 50% of young children after 10 days of antimicrobial therapy for acute otitis media. Pathogenic bacteria are present in at least 25% of such effusions. We studied the effect of a 2-week course of trimethoprim-sulfamethoxazole (TMP-SMX) administered to 33 children who had POME and compared the results obtained to those of a similar group of children with POME who did not receive drug therapy. This study was designed to answer two questions: (1) Would TMP-SMX promote the resolution of POME? (2) Would TMP-SMX prevent an attack of acute otitis media (AOM) superimposed on POME? The diagnosis of POME was validated by obtaining a type B tympanogram, and AOM was diagnosed according to strict criteria. Each child was randomly assigned either to a treatment group that received a 14-day course of TMP-SMX or to a control group that received no medication. TMP-SMX failed to promote resolution of POME but did prevent recurrent AOM. During the second 2-week (follow-up) phase of the study, when no antimicrobial was given to either subject group, the incidence of AOM was similar in both groups.