The perinatal histories and hospital courses of all neonates born at Grady Memorial Hospital who developed Pseudomonas aeruginosa sepsis or meningitis in the 5-year period 1989-1993 were reviewed. In addition a case-control study was performed to evaluate selected risk factors for this infection. Twenty-one patients had one or more blood cultures positive for P. aeruginosa. An additional patient had P. aeruginosa meningitis without bacteremia. All infections occurred after 5 days of age. The overall incidence of P. aeruginosa infection was 0.7/1000 live births. All cases occurred in infants < 1500 g at birth, for a birth weight-specific rate of 19.5/1000 livebirths in this weight class. Clinical manifestations of disease did not distinguish P. aeruginosa from other causes of fulminant neonatal sepsis. Fifty percent of cases died. Mortality was inversely related to postnatal age at diagnosis. The 22 cases were compared with 44 controls matched for birth weight, gestational age, sex, duration of hospital stay and admission date. Cases were more likely than controls to have a history of feeding intolerance, interrupted enteral intake and prolonged parenteral hyperalimentation. Case infants received intravenous antibiotics for a significantly longer period of time than did controls. There was an association between P. aeruginosa sepsis and necrotizing enterocolitis (36% cases vs. 7% of controls had prior or concurrent necrotizing enterocolitis, P < 0.01). In summary P. aeruginosa sepsis is primarily a late onset nosocomial infection in very low birth weight infants. The case fatality rate of 50% in this series emphasizes its continued importance.