Bilomas, infected hepatic fluid collections, are a frequent complication of liver transplantation. We report a case-control cohort study to determine the incidence and microbiologic profile of bilomas and risk factors for biloma formation in 492 patients undergoing liver transplantation from 1994 to 2001. Fifty-seven patients (11.5%) developed one or more bilomas; 95% in the first year post-transplantation. The most common initial infecting pathogens were enterococci (37%), one-half resistant to vancomycin (VRE); coagulase-negative staphylococci (26%); and Candida species (26%). Infection by coagulase-negative staphylococci was strongly associated with the presence of a T-tube (OR 9.60, p = 0.02). In stepwise logistic regression multivariable analyses, hepatic artery thrombosis (OR 90.9, p < 0.0001), hepatic artery stenosis (OR 13.2, p < 0.0001) and Roux-en-Y choledochojejunostomy (OR 5.8, p = 0.03) were independent risk factors for biloma formation; ursodeoxycholic acid use was highly protective (OR 0.1, p = 0.002). Strategies to prevent biloma formation must focus on measures to prevent hepatic artery thrombosis and colonization of liver transplant patients by multiresistant nosocomial pathogens. T-tube drainage post-transplantation bears reassessment. The protective effect of ursodeoxycholic acid found in this study warrants confirmation in a prospective multicenter, randomized trial.