The aim of this retrospective study was to investigate if the application of chlorhexidine-based solutions (ChloraPrep) to the exit site and the hub of long-term hemodialysis catheters could prevent catheter-related bacteremia (CRB) and prolong catheter survival when compared with povidone-iodine solutions. There were 20,784 catheter days observed. Povidone-iodine solutions (Betadine) were used in the first half of the study and ChloraPrep was used in the second half for all the patients. Both groups received chlorhexidine-impregnated dressings at the exit sites. The use of ChloraPrep significantly decreased the incidence of CRB (1.0 vs 2.2/1,000 catheter days, respectively, P = 0.0415), and hospitalization due to CRB (1.8 days vs 4.1 days/1,000 catheter days, respectively, P = 0.0416). The incidence of exit site infection was similar for the two groups. Both the period of overall catheter survival (207.6 days vs 161.1 days, P = 0.0535) and that of infection-free catheter survival (122.0 days vs 106.9 days, P = 0.1100) tended to be longer for the catheters cleansed with ChloraPrep, with no statistical significance. In conclusion, chlorhexidine-based solutions are more effective for the prevention of CRB than povidone-iodine solutions. This positive impact cannot be explained by decreased number of exit site infections. This study supports the notion that the catheter hub is the entry site for CRB.