To identify predictors of infection in catheters used for total parenteral nutrition (TPN), clinical and microbiological data were prospectively collected on 169 catheter systems (88 patients). Based on semiquantitative catheter cultures, infection was associated with a positive insertion site skin culture taken close to the time of catheter removal (relative risk [RR] = 4.50), especially one yielding greater than or equal to 50 colonies of an organism other than coagulase-negative staphylococci. Infection was also associated with erythema at the insertion site greater than 4 mm in diameter (RR = 2.93). In a subset of 67 catheters for which blood cultures were obtained, infection was also associated with a positive peripheral venous blood culture (RR = 5.90) and a positive central venous blood culture obtained through the catheter (RR = 5.44). Based on a logistic regression model, periodic cultures of the insertion site should be useful in evaluating subsequent fever in stable patients with indwelling central venous catheters. Another source of fever is likely if inflammation is absent and there is either no colonization or there is colonization by less than 50 colonies of coagulase-negative staphylococci at the insertion site. Conversely, the catheter should be removed and cultured semiquantitatively if the site is colonized by an organism other than coagulase-negative staphylococci. We suggest that blood culture results add little to the risk estimate in these situations.