Purpose: The aim of the study was to investigate the effect of prophylactic cycling of parenteral nutrition (PN) on PN-induced cholestasis in patients with gastroschisis. Methods: Retrospective review of initial hospital admission charts for each patient with gastroschisis from 1996 to 2007 was performed. Results: One hundred seven patients were analyzed (36 prophylactically cycled, 71 control). Prophylactic cycling of PN was initiated at a mean age of 23 days (range, 7-89 days). Patients were followed for a total of 4255 days with 27 developing hyperbilirubinemia (cycled, 5; continuous, 22). Time to hyperbilirubinemia was longer in the prophylactically cycled group (P = .005). Cumulative incidence of hyperbilirubinemia at 25 and 50 days of PN exposure was 5.7% and 9.8% (cycled) vs 22.3% and 48.8% (continuous). At any given time, children in the continuous group were 4.76 times more likely to develop hyperbilirubinemia (95% confidence interval, 1.62-14.00). After adjusting for confounding factors, children in the continuous group were 2.86 times more likely to develop hyperbilirubinemia (95% confidence interval, 0.86-9.53), but the difference was not significant (P = .088). Conclusions: Prophylactic cyclic PN is associated with a decreased incidence and prolonged time to onset of hyperbilirubinemia. Other factors, however, significantly affect this relationship. Prospective randomized investigation is warranted to investigate for a possible causal relationship.