The dominant problem associated with the use of tunneled-cuffed catheters is infection. When this occurs, two issues must be addressed: treatment of the infection and management of the catheter. The purpose of this 2-yr study was to report the results of a prospective observational series in which catheter management was based on the clinical picture presented by the patient. Data were collected on patients with catheter-related bacteremia (CRB) dealt with in one of three ways: (1) minimal symptoms with a normal-appearing tunnel and exit site (exchange over guidewire within 48 h of antibiotic initiation [Xchng group], 49 cases); (2) minimal symptoms but with tunnel or exit site infection (exchange over a guidewire with creation of a new tunnel [Nutunl group], 28 cases); and (3) severe clinical symptoms (catheter removal with delayed replacement after defervescence [Delay group], 37 cases). All cases were treated immediately with empiric antibiotics followed by 3 wk of antibiotic therapy based on culture sensitivities. A cure was defined as a 45-d symptom-free interval after antibiotic therapy was complete. A cure rate total of 87.8% for the Xchng group, 75% for the Nutunl group, and 86.5% for the Delay group was seen for the 114 episodes of CRB. It is concluded that in selected patients, catheter exchange over a guidewire within 48 h of antibiotic initiation followed by 3 wk of specific antibiotic therapy is a viable treatment option. Additionally, replacing the catheter in patients presenting with severe symptoms of sepsis as soon as they have defervesced is a reasonable approach to therapy.