Background: Data on the efficacy of particular therapeutic protocols of interferon-α (IFN-α) treatment for chronic hepatitis C in patients on hemodialysis (HD) vary. Aim: To compare the efficacy of two different therapeutic protocols for HD patients. Patients and Methods: 15 hepatitis C virus (HCV)-positive patients on chronic HD at two dialysis centers: 8 patients treated with IFN-α 3 × 3 MU/week s.c. for 6 months (group A), and 7 patients treated with IFN-α 3 × 5 MU/week for 3 months, then 1 × 5 MU/week for another 3 months (group B). End of treatment response (ETR) and sustained virologic response (SVR) were evaluated by HCV-RNA determination. There was no statistically significant difference between the two patient groups according to age, sex, duration of HD and HCV infection. Results: ETR was 87.5% (7/8) in group A and 28.5% (2/7) in group B, being statistically significant (p < 0.05). Although better SVR [50% (4/8) vs. 28.5% (2/7)] and lower drop-out rate [0% (0/8) vs. 28.5% (2/7)] were achieved in group A compared to group B, these differences did not reach statistical significance (p > 0.05). Conclusion: Therapy with IFN-α 3 × 3 MU/week s.c. for 6 months seems to be more appropriate for treatment of hepatitis C in HD patients, mostly due to better tolerability, i.e. lower drop-out rate. These differences could be attributed to different pharmacokinetic properties of the particular therapy protocol.