To identify factors associated with antimicrobial resistance, data were analyzed from 27,828 isolates of Streptococcus pneumoniae submitted to the Tracking Resistance in the United States Today ( TRUST) surveillance program during 4 consecutive respiratory seasons. From the 1998-1999 season to the 2001-2002 season, the prevalence of azithromycin resistance increased by 4.8% to 27.5%, the prevalence of penicillin resistance increased by 3.7% to 18.4%, the prevalence of ceftriaxone resistance increased by 0.5% to 1.7%, and the prevalence of levofloxacin resistance increased by 0.3% to 0.9%. Isolates recovered from patients <18 years of age and lower respiratory tract specimens had elevated rates of penicillin, azithromycin, and trimethoprimsulfamethoxazole resistance (P<.00001); penicillin resistance correlated with coresistance to trimethoprimsulfamethoxazole (87.3%), azithromycin (76.3%), ceftriaxone ( 9.1%), and levofloxacin (1.3%) (P<.00001). Only 62 (0.2%) of 27,828 isolates were concurrently resistant to penicillin and levofloxacin. Minimum inhibitory concentrations (MICs) of penicillin correlated strongly with MICs of ceftriaxone (R-2=0.90), trimethoprimsulfamethoxazole (R-2=0.53), and azithromycin (R-2=0.41). Patient age, specimen source, and penicillin resistance were factors associated with antimicrobial resistance, particularly for nonfluoroquinolone antimicrobial agents.