We report 70 total parenteral nutrition (TPN) patients who received guidewire catheter exchange for suspected sepsis during their hospitalization. To diagnose catheter-related sepsis (CRS) and catheter infection (CI), we used a system of pre- and postexchange catheter blood cultures and a catheter tip culture. There were 27 catheter exchanges with positive cultures. The rate of definite CRS/CI (eight instances) was 6.8% of catheters exchanged and 3.5% of all catheters at risk. Probable CRS/CI (11 instances) was seen in 9% of exchanged catheters and 5% of at risk catheters. Thus, 19/27 positive cultures were presumed to represent definite or probable CRS/CI. Coagulase negative Staphylococcus (SCN) was the most frequently isolated organism. Simple catheter exchange was usually effective treatment of CRS/CI when SCN was the offending organism. The salvage rate of catheters exchanged for suspected sepsis or after a positive blood culture was 84%. Only 7% of exchanged catheters had to be removed. Guidewire exchange with triple culture technique was without mechanical complications. We recommend this technique to monitor central venous catheters in patients receiving TPN since it is simple, essentially painless to perform, and easily interpreted.