Background Noncuffed, percutaneously inserted central venous catheters (CVCs) are widely used and cause at least 250,000 bloodstream infections (BSIs) in U.S. hospitals each year. We report a prospective study to determine whether inflammation at the insertion site is predictive of CVC-related BSI. Methods Percutaneously inserted, noncuffed CVCs inserted into the subclavian, internal jugular, or femoral vein in two randomized trials during 1998–2000 were prospectively studied; most patients were in an intensive care unit. The condition of the insertion site was evaluated daily by research nurses, quantifying pain (0, 1), erythema (0–2), swelling (0, 1), and purulence (0, 1); the lowest possible overall inflammation score was 0 and the highest was 5. CVC-related BSI was confirmed in each case by demonstrating concordance between isolates from the catheter segment and from blood cultures by restriction-fragment DNA subtyping. Results Among 1,263 CVCs prospectively studied, 333 (26.3%) were colonized at removal; of these, 35 catheters (2.7%) caused BSIs (5.9 per 1000 CVC days). BSIs were caused by coagulase-negative staphylococci (n = 27), enterococci (n = 4), enteric Gram-negative bacilli (n = 3), or Candida (n = 1). Most insertion sites showed little or no inflammation at the time of removal. There were no significant differences among mean scores for each inflammatory variable examined or overall score among colonized CVCs (0.1 ± 0.1), catheters causing CVC-related BSI (0.2 ± 0.4), and noncolonized CVCs (0.1 ± 0.1). The sensitivity of local inflammation for diagnosis of CVC-related BSI was dismal (0–3%). Conclusion Local inflammation is uncommon with infected CVCs, probably because most catheter-associated infections are currently caused by coagulase-negative staphylococci, a pathogen that incites little local or systemic inflammation. Whereas overt inflammation of the insertion site should raise suspicion of CVC-related BSI caused by Staphylococcus aureus or Gram-negative bacilli, especially if the patient has fever or other signs of sepsis, in general, site appearance cannot be relied on to identify catheter colonization or CVC-related BSI.