Thirty-one patients with suspected central venous catheter-related bacteremia were evaluated with comparative quantitative cultures of central venous and peripheral blood specimens. Using criteria developed from studies in bacteremic animals, 19 patients were confirmed to have catheter-related bacteremia. Antibiotic therapy was administered through the catheter (in situ therapy) in 17 of those patients to evaluate the feasibility of treating patients with true central venous catheter-related bacteremias without catheter removal. Bacteremia was successfully eradicated in 11 of 17 patients (65%), allowing 7 patients to retain their catheter a median of 157 days. This study validates the use of comparative quantitative blood cultures in the diagnosis of catheter-related bacteremia and indicates that in situ therapy is a rational alternative to catheter removal in patients with catheter-related bacteremia.