OBJECTIVE To investigate whether intermittent short-term courses of penicillin V (PcV) administered as intermittent prophylaxis against acute otitis media (AOM) during upper respiratory tract infections altered the nasopharyngeal bacterial flora and/or its susceptibility to penicillin. METHODS In a double blind, placebo controlled study 70 children (30 in the PcV group and 40 in the placebo group) were followed for 1 year. At episodes of upper respiratory tract infection the children were given PcV or placebo and then seen by one of the investigators within 3 days. The tympanic membranes were examined by otomicroscopy and a culture from the nasopharynx was obtained. If AOM was found PcV was given (25 mg/kg bw b.i.d) for 5 days. If the child presented normal eardrums or signs of secretory otitis media (SOM) the study treatment was continued for a total of 5 days. All children were also examined bimonthly throughout the study irrespective of episodes of URTI or AOM. RESULTS No increase in the number of isolates of S. pneumoniae with reduced susceptibility to penicillin (MIC> or =0.125 mg/l) was noted in either group compared with the incidence in the population in Sweden at the time of the study (when ca. 10% of pneumococci had a reduced susceptibility to penicillin). The number of cultures positive for S. pneumoniae were statistically reduced in children during treatment with PcV compared with children receiving placebo, while the number of cultures positive for H. influenzae and M. catarrhalis were unaffected. No increase in the number of cultures positive for beta-lactamase producing H. influenzae was noted (ca. 10%). CONCLUSIONS Repetitive short term PcV courses during URTI in infants did not increase the number of cultures positive for S. pneumoniae with reduced susceptibility to penicillin or beta-lactamase producing H. influenzae.