For identification of risk factors for bloodstream infection (BSI) among neonatal intensive care unit patients, prospective 6-month studies in three neonatal intensive care units were conducted. BSI was diagnosed in 42 of 376 (11.2%) enrolled infants. Pathogens included coagulase-negative staphylococci, Candida sp., Group B streptococci and Gram-negative species. Patients with BSIs were more likely to die during their neonatal intensive care unit stay than were patients who did not acquire BSIs (6 of 42 vs. 11 of 334, P = 0.007). BSI rate was highest in infants with birth weight < 1500 g (relative risk (RR) = 6.8, P < 0.001), those treated with H-2 blockers (RR = 4.2, P < 0.001) or theophylline (RR = 2.8, P < 0.001) and those with admission diagnoses referable to the respiratory tract (RR = 3.7, P < 0.001). Infants who developed BSI were more severely ill on admission than other infants (median physiologic stability index 13 vs. 10 (P < 0.001) and were of lower gestational age (28 vs. 35 weeks, P < 0.001). In logistic regression analysis, risk of BSI was independently associated only with very low birth weight, respiratory admission diagnoses and receipt of H-2 blockers. Risk of isolation of a pathogen from blood culture was independently associated with Broviac, umbilical vein or peripheral venous catheterization > 10, 7 or 3 days, respectively, at one insertion site. Rate of isolation of a pathogen was higher (9 of 59 (15%)) within 48 hours of a measurable serum interleukin 6 concentration than an interleukin 6 level of 0 pg/ml (10 of 159 (6%), P = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)