The in vitro activity of five cephalosporins, gentamicin, and vancomycin was determined against 41 clinical isolates of methicillin-resistant, coagulase-negative staphylococci. Results obtained with disk diffusion and agar dilution methods failed to show complete cross-resistance between methicillin and four of the five cephalosporins despite the use of a high-salt medium and a large inoculum. Thirty-six (88%) of the 41 isolates were sensitive to cephalothin by a standardized disk diffusion method, whereas 23 isolates (56%) were sensitive to cephalothin with use of an agar dilution method and a large inoculum. Of these 23 isolates, only 11 (47%) were both inhibited and killed by less than or equal to 6.25 microgram of cephalothin/ml. The inhibitory and bactericidal activity of gentamicin was greater than that of vancomycin and cephalothin. These results suggest that the disk diffusion technique has limitations in determining the in vitro activity of cephalosporins against methicillin-resistant, coagulase-negative staphylococci and that cephalothin exhibits poor bactericidal activity against these same isolates.