Coagulase-negative staphylococci are infrequently recognized as pathogens responsible for life-threatening nosocomial infections in high-risk neonates. To determine the incidence, appearance, and antibiotic sensitivity of infections with these organisms, 416 infants were surveyed. Fifty infants (12%) had blood cultures positive for coagulase-negative Staphylococcus. Fourteen cultures (13 infants; mean birth weight +/- SD, 1.91 +/- 1.13 kg; gestational age +/- SD, 34 +/- 6 weeks) were identified as representing true bacteremia (pure growth of the organism in both bottles of one or more blood cultures exhibiting identical antibiotic sensitivities). Twelve cultures exhibited clinical signs of sepsis, and WBC counts were suggestive of sepsis in seven cases. Thirteen organisms were penicillin resistant, eight were oxacillin resistant, and all were sensitive to vancomycin. Coagulase-negative staphylococci are currently the most common nosocomial pathogens at our hospital. Therapy for suspected coagulase-negative staphylococcal sepsis should include vancomycin hydrochloride.