We evaluated the antimicrobial spectrum and potency of cefepime and selected comparators agents against clinical bacterial strains collected in North America over a 6-year period (1998-2003). Isolates were consecutively collected from bloodstream (44%), respiratory tract (41%), urinary tract (6%), and skin/soft tissue (5%) infections in 48 medical centers. Isolates were susceptibility tested by reference broth microdilution methods in a central laboratory. Oxacillin-resistant staphylococci and enterococci were excluded from the analysis. Imipenem (MIC90 = 1 microg/mL, 99.9% susceptible) was the most active compound tested against Enterobacteriaceae (22860 isolates tested) followed by cefepime (MIC90 = 0.25 microg/mL, 99.5% susceptible) > amikacin (99.4% susceptible) > ceftriaxone (95.6% susceptible) > aztreonam (95.1% susceptible). Among comparators, the lowest susceptibility rate for Enterobacteriaceae was observed with ciprofloxacin (92.8% susceptible). Imipenem was also the most active compound against ESBL-producing Klebsiella spp. and Escherichia coli (99.3% and 100% susceptible, respectively), followed by amikacin (81.4% and 97.2% susceptible, respectively) and cefepime (92.5% and 93.8% susceptible, respectively). Cefepime activity against Pseudomonas aeruginosa (85.2% susceptible) was similar to that of imipenem (86.9% susceptible). Against oxacillin-susceptible Staphylococcus aureus, cefepime (MIC90 = 4 microg/mL, 100.0% susceptible) was 4-fold more active than ceftazidime (MIC90 = 16 microg/mL, 86.4% susceptible) and showed a higher susceptibility rate than ciprofloxacin (93.2% susceptible). Cefepime was the most active compound tested against Streptococcus pneumoniae (MIC90 = 1 microg/mL, 97.4% susceptible), ranked after gatifloxacin and levofloxacin (99.2% susceptible). The activity of cefepime remained stable during the study period evaluated with the susceptibility rates varying from 99.3% to 99.8% among the Enterobacteriaceae and 84.4% to 88.4% among P. aeruginosa isolates. In summary, cefepime has retained broad activity and spectrum against Enterobacteriaceae, P. aeruginosa, and Gram-positive cocci (except oxacillin-resistant staphylococci and enterococci) isolated from North American medical centers in the 1998-2003 period. Continued resistance surveillance is critical to monitor the effectiveness of widely used parenteral antimicrobial agents such as cefepime.