Dialysis catheter-related bacteremia (CRB) can frequently be treated with systemic antibiotics, in conjunction with an antibiotic lock, in an attempt to salvage the catheter. It is unknown whether CRB associated with an exit-site infection can be treated with such an approach. We retrospectively queried a prospective, computerized vascular access database, and identified 1436 episodes of CRB, of which 64 cases had a concurrent exit site. The frequency of concurrent exit-site infection was 9.6% with Staphylococcus epidermidis, 6.1% with Staphylococcus aureus, and only 0.7% with Gram negative CRB (p < 0.001 for Staphylococcus vs. Gram negative rods). Five serious complications (four major sepses and one endocarditis) occurred in 24 patients with S. aureus infection, but none in 32 episodes of S. epidermidis infection (p = 0.01). Catheter survival was significantly shorter in patients with S. aureus infections. The median catheter survival (without infection or dysfunction) was 14 days with S. aureus vs. 30 days with S. epidermidis infection (p = 0.035). In conclusion, concurrent exit-site infection is seen most commonly in association with Staphylococcal CRB. When the infecting organism is S. epidermidis, attempted salvage with systemic antibiotics and an antibiotic lock is reasonable. However, prompt catheter removal is indicated when the pathogen is S. aureus.