The association between periventricular-intraventricular hemorrhage (PV-IVH) and frequent handling resulting from various neonatal intensive care procedures and routine interventions was evaluated in a prospective clinical study. Inborn premature babies with birth weight less than or equal to 1500 gm (n = 156) who did not have PV-IVH or who had grade 1 PV-IVH at less than or equal to 1 hour were randomly assigned to the reduced manipulation protocol (n = 62) or to standard care (n = 94). A bedside microcomputer-based data acquisition system was used to monitor the duration of rest or the number of interventions per day. Infants assigned to receive reduced manipulation spent a significantly higher percentage of time each day at rest than did those who received standard manipulation (p less than 0.006). However, the incidence of grades 2 to 4 PV-IVH did not differ significantly (30% in the study vs 37% in the standard manipulation group). When we analyzed the effect of manipulation in relation to risk of PV-IVH, while taking into account other perinatal variables, standard manipulation was not associated with increased risk of grades 2 to 4 PV-IVH. However, low birth weight, maternal smoking, general anesthesia, early grade 1 PV-IVH, low hematocrit, lowest arterial oxygen pressure within the first 6 hours of life, and large base deficit at 6 hours of age all increased the relative risk of grades 2 to 4 PV-IVH.