Objective: To determine the factors associated with an increasing rate of nosocomial infections in infants with very low birth weights. Methods: Retrospective review of clinical and nosocomial infection databases for all infants with birth weights of 1500 g or less admitted to an academic neonatal intensive care unit between January 1, 1991, and December 31, 1997 (N=1184). Two study periods were compared: 1991-1995 and 1996-1997. Results: Among the 1085 infants who survived beyond 48 hours, the proportion who developed nosocomial infections increased from 22% to 31% (P=.001) and the infection rate increased from 0.5 to 0.8 per 100 patientdays (P<001) during the period from 1996 to 1997. In that same period, the median duration of indwelling vascular access increased from 10 to 16 days (P<001), and the median duration of mechanical ventilation increased from 7 to 12 days (P<001). Although the device-specific rate of bloodstream or respiratory infections did not change, the increase in infections was directly attributable to the increasing proportion of infants who required these devices. In both study periods, the peak incidence of initial infection occurred between 10 and 20 days of age. For the entire sample, proportional hazard models identified birth weight, duration of vascular access, and postnatal corticosteroid exposure as significant contributors to the risk of infection. Conclusions: The increasing number of technology-dependent infants was the primary determinant in the increase of nosocomial infections. Because these infections occur in a small proportion of infants, understanding the host factors that contribute to this vulnerability is necessary to decrease nosocomial infections in neonatal intensive care units.