Abstract The predicted sensitivities of common organisms guide initial antibiotic therapy in endophthalmitis. The authors suspected a change in the expected sensitivity of coagulase-negative staphylococci when three cases of endophthalmitis due to multiply resistant organisms failed to respond to intravitreal cefazolin and gentamicin. The authors reviewed 48 cases from 1982 to 1986, compared these with 28 cases from 1973 to 1981, they found increased resistance to gentamicin (35 versus 0%, P < 0.05) and increased resistance to methicillin (27 versus 19%). Eight cases were resistant to both antibiotics, including the three clinical failures. Final vision was unrelated to antimicrobial resistance. Since cephalosporins may be ineffective clinically against methicillin-resistant staphylococci, concomitant gentamicin resistance may render intravitreal cefazolin and gentamicin inadequate for their treatment. No isolates were resistant to vancomycin. Vancomycin and aminoglycoside, used intravitreally in the initial management of endophthalmitis, would be anticipated to provide better coverage than cefazolin and aminoglycoside for endophthalmitis due to the staphylococci, as well as for infections due to streptococcal and bacillus species.