Technical Abstract: Objective. To determine whether cholecystokinin-octapeptide (CCK-OP) would prevent or ameliorate parenteral nutrition-associated cholestasis (PNAC) among high-risk neonates treated with total parenteral nutrition. Study Design. This was a multicenter, double-blind, randomized, controlled trial conducted between 1996 and 2001. Patients. Neonates at risk for the development of PNAC included very low birth weight neonates and those with major surgical conditions involving the gastrointestinal tract. Setting. Tertiary care hospitals. Intervention: Patients were randomized to receive CCK-OP (0.04 'g/kg per dose, twice daily) or placebo. Eligible infants were all <30 days of age. Patients were enrolled within 2 weeks after birth or within 7 days after surgery. Outcome Measures. The primary outcome measure was conjugated bilirubin (CB) levels, which were measured weekly. Secondary outcome measures included incidence of sepsis, times to achieve 50% and 100% of energy intake through the enteral route, number of ICU and hospital days, mortality rate, and incidences of biliary sludge and cholelithiasis. Results. A total of 243 neonates were enrolled in the study. CCK-OP administration did not significantly affect CB levels (1.76 +/- 3.14 and 1.93 +/- 3.31 mg/dL for CCK-OP and placebo groups, respectively; mean +/- SD). Secondary outcome measures also were not significantly affected by the study drug. Conclusions. Use of CCK-OP failed to reduce significantly the incidence of PNAC or levels of CB. CCK-OP had no effect on other secondary measures and should not be recommended for the prevention of PNAC.