With increasing pneumococcal resistance to penicillin and other antibiotics, use of antibiotic therapy for children with upper respiratory tract infections such as otitis media and sinusitis has become difficult. Selecting an appropriate treatment regimen has become more challenging due to frequent concomitant microbial resistance to multiple antibiotics. In a prospective, nonrandomized study, we obtained middle ear and sinus aspirate specimens from all children undergoing outpatient tympanocentesis or sinus lavage for any indication at our institution over two 4-week periods. One hundred fifty-four specimens were obtained. Of these, 12 grew Streptococcus pneumoniae, 7 of which were resistant to penicillin. A 6-month retrospective review of these patients' medical histories evaluated their antibiotic use prior to surgical intervention. An association between penicillin resistance and recent use of 2 or more antibiotics in children with positive S pneumoniae cultures was confirmed, as has been documented in prior reports. Those with penicillin-resistant S pneumoniae also demonstrated a higher incidence of multidrug-resistant organisms.