We undertook to identify the antimicrobial susceptibility of the pathogens isolated from patients with otitis media or maxillary sinusitis who failed to respond to antimicrobial therapy, and correlate it with previous antimicrobial therapy and smoking. We analyzed isolates recovered from 2 consecutive cultures obtained from middle ear aspirate obtained through an open perforation in 22 children with otitis, and maxillary sinus aspirate collected by endoscopy from 20 patients. Forty-seven isolates were repeatedly recovered from 42 culture-positive individuals. The organisms isolated were Streptococcus pneumoniae (15 isolates), Haemophilus influenzae (14), Staphylococcus aureus (7), Moraxella catarrhalis (6), and Streptococcus pyogenes (5). Resistance of at least 2 tube dilutions to the antimicrobial agents used was found in 23 of the 47 (49%) isolates that were found in 20 (48%) of the patients. These included 10 of 15 (67%) isolates of S pneumoniae, 4 of 14 (29%) H influenzae (all were beta-lactamase producers), 4 of 7 (57%) S aureus (all beta-lactamase producers), 5 of 6 (83%) M catarrhalis (all beta-lactamase producers), and none of 5 S pyogenes. In the 21 patients who failed to respond to amoxicillin, H influenzae and S pneumoniae predominated. Streptococcus pneumoniae was recovered from 4 of the 11 (36%) after trimethoprim-sulfamethoxazole, 4 of 21 (19%) after amoxicillin, 2 of 3 (67%) after azithromycin dihydrate, and 1 of 4 (25%) after cefixime. A statistically significant higher recovery of resistant organisms was noted in those treated 2 to 6 months previously, and in those with sinusitis who smoked. The data illustrate the relationship between resistance to antimicrobials and failure of patients with otitis media and sinusitis to improve.