Laboratory criteria were used to select coagulase-negative staphylococci isolated from nonsterile body sites for further investigation. Fifty-seven percent of the study isolates were clinically significant, predominantly causing community-acquired soft tissue infections. There were species-related differences in virulence, with 91% of Staphylococcus lugdunensis isolates clinically significant compared with 11% of S. haemolyticus isolates.