After two intramuscular (IM) vaccination protocols (40 microg at 0, 1, 2, and 6 months), patients who were unresponsive to hepatitis B vaccination were collected from three HD centers. The aim of this study was to compare the effectiveness of intradermal (ID) and repeated IM vaccination protocols. Thirty-three of 639 HD patients were found to be unresponsive. Patients were randomly assigned into two groups: one to receive 80 microg ID and the other 160 microg IM vaccination protocol. Both ID (p = 0.000) and IM (p = 0.03) groups disclosed statistically significant seroconversion rates six months after the last vaccination dose. The seroconversion rate was 94.1% in the ID and 50% in the IM groups - showing a significant improvement in the ID group (p = 0.011). A low-dose ID is superior to standard IM vaccination protocol and also more cost-effective in unresponsive HD patients.