We tested 83 penicillin-intermediate (Pen(i)) and 50 penicillin- resistant (Pen(r)) isolates of Streptococcus pneumoniae against eight oral antimicrobials. Clarithromycin's MICs (minimal inhibitory concentration) were generally the same or one to two dilutions less than those of azithromycin. Seventy-two percent of Pen(i) isolates were susceptible to clarithromycin and azithromycin, in contrast to 42% and 40%, respectively, of Pen(r) isolates. Cefuroxime activity exceeded that of cefprozil, which exceeded that of cefaclor, in Pen(i) isolates. For all three cephalosporins, MICs of 90% of isolates tested were ≤3 dilutions higher for Pen(r) isolates than for Pen(i) isolates. Percentages of Pen(i) isolates susceptible to clindamycin and tetracycline were 92% and 83%, respectively, and 78% and 82% for Pen(r). Only 49% of Pen(i) isolates and 4% of Pen(r) isolates were susceptible to trimethoprim-sulfamethoxazole. Azithromycin, clarithromycin, cefuroxime, cefprozil, clindamycin, and tetracycline may be useful in treating infections caused by Pen(i) S pneumoniae, but Pen(r) isolates are frequently resistant to both old and newer agents.