The increasing prevalence of intermediately and highly penicillin-resistant strains ofStreptococcus pneumoniaeis a problem worldwide. However, optimal management of patients with middle ear and sinus infections caused by resistant pneumococci has not been established. We performed agar dilution susceptibility studies on 71 strains of penicillin-resistant pneumococci (minimum inhibitory concentration (MIC), ≥0.1 μg/ml) recovered from middle ear and sinus cultures of Houston children against 13 oral antibiotics with the use of both established and newly proposed National Committee for Clinical Laboratory Standards susceptibility criteria. Of the 62 middle ear isolates 35 (56%) were intermediately resistant and 27 (44%) were highly resistant to penicillin. Of the 9 sinus isolates tested, 5 (56%) were intermediately resistant (MIC between 0.1 and 1 μg/ml) and 4 (44%) were highly resistant (MIC ≥2 μg/ml) to penicillin. The MIC90increased with increasing penicillin resistance for the antibiotics tested except for rifampin, ciprofloxacin, loracarbef, clindamycin and trimethoprim-sulfamethoxazole. None of the highly penicillin-resistant isolates was susceptible to loracarbef or trimethoprim-sulfamethoxazole. The MIC90values for clindamycin and rifampin were similar for the intermediately and highly penicillin-resistant groups, and the number of susceptible isolates in each group remained greater than 90% for both antibiotics. Thirty-five isolates were resistant to erythromycin but susceptible to clindamycin, a susceptibility pattern distinctly different from that seen in South Africa and Europe, where clindamycin resistance parallels erythromycin resistance. Further study is necessary to correlatein vitrosusceptibility data with clinical outcome from infections caused by penicillin-resistant pneumococci because the MIC90values for most of the antibiotics tested against the isolates in our study exceeded achievable antibiotic concentrations in middle ear effusions.