Catheter-related infections are a major cause of morbidity and mortality in hemodialysis (HD) patients. This study evaluated the utility of surveillance swab cultures (Ssc) of tunneled cuffed catheter (TCC) exit sites as a prediction and prevention strategy for infection. A 6-month prospective-controlled trial with 94 chronic HD patients with a TCC who received monthly Ssc and were stratified by dialysis day into topical therapy based on Ssc results (Group A) or no therapy (Group B). Outcomes were exit site infection (ESI) and catheter-associated bacteremia (CAB). The overall monthly prevalence of positive Ssc was 14.9%. There was no difference in the number of positive Ssc (17.7% vs. 11.6%, p > 0.05) or ESI (19.6% vs.16.3%, p > 0.05) between Groups A and B, respectively. Catheter-associated bacteremia was higher in Group A (17.7% vs. 4.7%, p = 0.05). There were significantly more ESI in the patients treated for a positive Ssc. In Group A, the incidence of ESI was significantly higher in those treated for a positive vs. negative Ssc (55% vs. 12%, p = 0.009) and CAB rates trended higher with positive Ssc (22.2% vs. 16.7%, p > 0.05). The strategy of treating positive surveillance cultures is not beneficial. Positive Ssc do not predict the occurrence of catheter-related infection, and treatment of these cultures may lead to increased infection rates.