From 1997 to 1999, 94 study centers in 15 European, 3 North American, and 2 South American countries contributed 2,632 isolates of Streptococcus pneumoniae to an international antimicrobial susceptibility testing study. Only 62.0% of isolates were susceptible to penicillin, while 22.3% were penicillin intermediate and 15.6% were penicillin resistant. Resistance to trimethoprim-sulfamethoxazole (24.4%), azithromycin (26.0%), and clarithromycin (27.1%) was also highly prevalent. For the penicillin-resistant isolates (n ؍ 411), the MICs at which 90% of isolates are inhibited (MIC 90 s) for gemifloxacin, levofloxacin, ofloxacin, clarithromycin, and azithromycin were 0.03, 1, 2, >16, and >64 g/ml, respectively. Similarly, for isolates resistant to both azithromycin and clarithromycin (n ؍ 649), gemifloxacin, levofloxacin, ofloxacin, and penicillin MIC 90 s were 0.03, 1, 2, and 4 g/ml, respectively. Overall rates of resistance to trovafloxacin (0.3%), levofloxacin (0.3%), grepafloxacin (0.6%), and ofloxacin (0.7%) were low. For ofloxacin-intermediate and -resistant isolates (n ؍ 142), gemifloxacin had the lowest MIC 90 (0.12 g/ml) compared to the MIC 90 s of trovafloxacin (0.5 g/ml), grepafloxacin (1 g/ml), and levofloxacin (2 g/ml). For all S. pneumoniae isolates tested, gemifloxacin MICs were <0.5 g/ml, suggesting that gemifloxacin has the potential to be used as a treatment for pneumococcal infections, including those arising from isolates resistant to -lactams and macrolides.