We used four criteria to define true bloodstream infections after isolation of coagulase-negative staphylococci (CNS) from Isolator (Wampole Laboratories, Cranbury, NJ) blood cultures: (1) the patient's temperature was > or = 38 degrees C, (2) appropriate treatment was administered, (3) the physician diagnosed bloodstream infection or criteria for nosocomial bloodstream infection were met, and (4) at least one clinical sign or laboratory value was consistent with infection. Sixty (26.4%) of 227 episodes met these four criteria. By logistic regression, variables associated with meeting the definition of infection were admission to a service other than the surgical intensive care unit, the biotype of the Staphylococcus epidermidis isolates, the log of the weighted average of the total number of bacteria per milliliter of blood in all positive cultures, resistance to at least six antimicrobial agents, and the positivity of a BACTEC blood culture specimen that was drawn with the first positive Isolator culture specimen. In a high-risk population, 26% of Isolator blood cultures positive for CNS represented infections, a rate two to four times greater than that reported in the literature. Information regarding the species, biotype, antibiogram, and number of organisms per milliliter of blood might help physicians distinguish between CNS bloodstream infections and contamination.