A new approach for preventing and treating sepsis due to central venous catheter (CVC) has been devised at the Istituto Nazionale Tumori of Milan. A prospective protocol has been developed that includes the weekly exchange of the CVC via a guidewire as well as its exchange when a CVC-related sepsis is suspected. Growth of microorganisms on the tip of the CVC is defined as contamination if peripheral blood culture is negative and as sepsis if it is positive for the same microorganism. Colonization simply means growth of microorganism independently of the results of peripheral blood culture. Two hundred seven CVCs (64 polyvinyl chloride and 143 rubber silicone) were evaluated in 62 patients, for a total of 170 exchanges. The incidence of colonization and sepsis was 33.8% and 4.8%, respectively, a rate which is not significantly different from the values found in 81 historical controls (30.8% and 11.1%). However, it is noteworthy that the sepsis rate was reduced strongly during the first month of observation (0% vs. 11.9%; p = 0.01), whereas in the second month, it was similar in both groups (15% vs. 7.1%). Moreover, it should be noted that three-fourths of the colonized CVCs became negative after the first exchange, and virtually all were negative at the fourth exchange. All of the episodes of sepsis resolved spontaneously with the CVC exchange. The study, therefore, concludes that this procedure: 1) is without risk for CVC cross contamination, 2) is effective in the treatment of contaminated CVCs and of septic patients without any interruption of total parenteral nutrition, and 3) can reduce the incidence of CVC sepsis during the first month of total parenteral nutrition. One must be cautious about the possible onset of pulmonary embolism in patients with subclavian venous thrombosis, since a transient pulmonary embolism occurred in one of the patients. With the use of silastic CVCs, which are less thrombogenic than polyvinyl ones, the rate of pulmonary embolism due to blind exchange (without previous venography) is estimated to be 0.1% to 0.2%.