A total of 1,404 bacterial isolates were recovered from skin and soft tissue infections (SSTIs) from hospitalized patients in 24 sites in the United States (US) and 5 Canadian medical centers as part of the SENTRY Antimicrobial Surveillance Program. Isolates were collected between October and December, 2000. The rank order of pathogens was: Staphylococcus aureus (45.9%), Pseudomonas aeruginosa (10.8%), Enterococcus spp. (8.2%), Escherichia coli (7.0%), Enterobacter spp. (5.8%) and Klebsiella spp. (5.1%). The same order was observed in the US and Canada. Of note, almost 30% of S. aureus were oxacillin-resistant. Vancomycin resistance among enterococci was low (7.8%) representing a marked decrease from earlier SENTRY Program reports. Several antimicrobial agents remained very active against P. aeruginosa and Enterobacteriaceae isolates. In particular amikacin, cefepime, and the carbapenems (imipenem and meropenem) showed an excellent spectrum of activity (>95% susceptible). Extended-spectrum beta-lactamase production was observed in both E. coli (7.1%) and Klebsiella spp. (11.3%). Cefepime remained highly active, even against ceftazidime-resistant isolates of Enterobacter spp. The results of this study have identified the most common causes of SSTIs in hospitalized patients in North America, and can be used to make informed decisions concerning standards of empiric treatment for SSTIs in this region.