Introduction: Multiple cohort studies have shown an association between triple-lumen catheter use and catheter-related infections. We critically appraised the evidence to evaluate the risk of catheter-related sepsis with bacterial confirmation (CRSB) from multi-lumen compared with single-lumen central venous catheters. Methods: Studies were identified through MEDLINE and EMBASE (January 1980 through July 1998), the Cochrane Libraries, citation review of relevant primary and review articles, personal files and contact with expert informants. Through duplicate independent review, we selected randomized trials evaluating single versus multi-lumen catheters and their effect on complication rates. In duplicate, independently, we abstracted data on the population, catheter type, insertion and management details and outcomes. Results: We identified eight trials, five evaluating single versus double lumen (2 studies of umbilical venous catheters in critically ill neonates) and three evaluating single versus triple lumen catheters (critically ill adults). Use of multi-lumen catheters significantly decreased the need for peripheral venous access in 3 trials. Due to the low (≤ 1%) baseline infection rates, there was insufficient power to evaluate the CRSB risk of double versus single lumen catheters. In two trials in critically ill adults comparing triple to single lumen catheters, use of multiple lumens increased the risk of CRSB (RR 5.65, 95% CI 1.54, 20.79). In these studies, the single lumen port and one triple lumen port were dedicated exclusively to parenteral nutrition and the other two ports of the triple lumen catheter were accessed frequently for blood withdrawal and infusion of fluids and medications. In contrast, a third study found no difference in CRSB rates comparing triple to single lumen catheters (RR 1.11, 95% CI 0.34, 3.67) when multipurpose access of single and triple lumens was allowed. In this study, blood withdrawal was prohibited and single lumen catheters were in place an average of 2.5 days longer. Conclusions: Use of triple lumen catheters decreases the need for peripheral intravenous access. Unfortunately, frequent use of the additional lumens increases the risk of catheter-related sepsis.