Strategies for preventing central venous catheter (CVC)-related bloodstream infection are most likely to be effective if guided by an understanding of the risk factors associated with these infections. In this critical review of published studies of risk factors for CVC-related bloodstream infection that were prospective and used multivariable techniques of data analysis or that were randomized trials of a preventive measure, a significantly increased risk of catheter-related bloodstream infection was associated with inexperience of the operator and nurse-to-patient ratio in the intensive care unit, catheter insertion with less than maximal sterile barriers, placement of a CVC in the internal jugular or femoral vein rather than subclavian vein, placement in an old site by guidewire exchange, heavy colonization of the insertion site or contamination of a catheter hub, and duration of CVC placement > 7 days. Prospective studies or randomized trials of control measures focusing on these risk factors have been shown to reduce risk significantly: formal training in CVC insertion and care, use of maximal sterile barriers at insertion, use of chlorhexidine rather than povidone-iodine for cutaneous antisepsis, applying a topical anti-infective cream or ointment or a chlorhexidine-impregnated dressing to the insertion site, and the use of novel catheters with an anti-infective surface or a contamination resistant hub. Better prospective studies of sufficient size to address all potential risk factors, including insertion site and hub colonization, insertion technique, and details of follow-up care, would enhance our understanding of the pathogenesis of CVC-related bloodstream infection and guide efforts to develop more effective strategies for prevention.