Our purpose was to study prospectively the causes, routes of infection, and frequency of catheter-related sepsis in patients on total parenteral nutrition. From January 1981 to January 1984, cultures of 135 subclavian catheters from 135 adult patients were done by quantitative and semiquantitative methods. Twenty patients (14.8%) had catheter-related sepsis. Fourteen episodes (70%) stemmed from an colonized hub. Skin infection (Staphylococcus aureus, 2 cases), total parenteral nutrition mixture contamination (Enterobacter cloacae, 2 cases), and hematogenous seeding of the catheter tip (Yersinia enterocolitica, 1 case, and Streptococcus faecalis, 1 case) accounted for the remaining six septic episodes. The catheter hub is, in our experience, the most common site of origin of organisms causing catheter tip infection and bacteremia.