Bloodstream infection related to short-term use of noncuffed central venous catheters is a common and serious problem. Technologic innovations to reduce the risk for these infections are needed. To determine 1) the efficacy of a novel antiseptic catheter in preventing central venous catheter-related infection, 2) patient tolerance of this catheter, and 3) the sources of bloodstream infection originating from noncuffed, multilumen central venous catheters. Randomized, controlled clinical trial. Medical-surgical intensive care unit of a 450-bed university hospital. 158 adults scheduled to receive a central venous catheter; 403 catheters were studied. Participants received either a standard triple-lumen polyurethane catheter or a catheter that was indistinguishable from the standard catheter and was impregnated with chlorhexidine and silver sulfadiazine. Catheters were studied for colonization and catheter-related bloodstream infection at removal; local and systemic effects of catheters were assessed. The origin of each catheter-associated bloodstream infection was sought by culturing all potential sources (skin, catheter segments, hubs, and infusate) and confirmed by restriction-fragment DNA subtyping. Antiseptic catheters were less likely to be colonized at removal than control catheters (13.5 compared with 24.1 colonized catheters per 100 catheters; relative risk, 0.56 [95% CI, 0.36 to 0.89]; P = 0.005) and were nearly fivefold less likely to produce bloodstream infection (1.0 compared with 4.7 infections per 100 catheters; 1.6 compared with 7.6 infections per 1000 catheter-days; relative risk, 0.21 [CI, 0.03 to 0.95]; P = 0.03). In the control group, 8 catheter-related bloodstream infections were caused by Staphylococcus aureus, gram-negative bacilli, enterococci, or Candida species; no infections with these organisms occurred in the antiseptic catheter group (P = 0.003). No adverse effects from the antiseptic catheter were seen, and none of the 122 isolates obtained from infected catheters in either group showed in vitro resistance to chlorhexidine-silver sulfadiazine. Cost-benefit analysis indicated that the antiseptic catheter should prove cost-beneficial if an institution's rate of catheter-related bacteremia with noncuffed central venous catheters is at least 3 infections per 1000 catheter-days). The chlorhexidine-silver sulfadiazine catheter is well tolerated, reduces the incidence of catheter-related infection, extends the time that noncuffed central venous catheters can be safely left in place for the short term, and should allow cost savings.