Objective To observe the safety and immunogenicity of domestic freeze-dried rabies vaccine (human diploid cells, HDCs) for human use, shorten as HDCV. Methods The residents at ages of 10-60 years in Lianshui County, Huai'an City, Jiangsu Province, China, at high risk of rabies virus infection, were divided into trial and control groups, 600 for each. The subjects in trial group were immunized i.m. with domestic freeze-dried HDCV according to Essen schedule on days 0, 3, 7, 14 and 28 resp., while those in control group with imported freeze-dried rabies vaccine for human use (Vero cells). All the subjects were observed for immediate reaction for 30 min, and for local and systemic reactions 6, 24, 48 and 72 h after immunization. Serum samples were collected before and 7, 14, 42 d after immunization, and determined for neutralizing antibody by rapid fluorescent focus inhibition test (RFFIT), based on which the pos. conversion rate and geometric mean titer (GMT) of antibody were calculated Results All the adverse reactions in subjects were mild and disappeared within 72 h, while no reactions of grade III or above were observed The total incidence rates of local reactions in trial and control groups were 7.67% and 6.83% resp., while those of systemic reactions were both 5.00%, which showed no significant difference (P > 0.05). The antibody pos. conversion rates in trial group 7, 14 and 42 d after the first dose were 28.77%, 100% and 100%, while those in control group were 28.72%, 98.96% and 100%, resp., which showed no significant difference (P > 0.05). However, the GMTs of antibody in trial group 7, 14 and 42 d after the first dose were 0.2748, 19.7443 and 37.5750 IU/mL, while those in control group were 0.2474, 17.3274 and 37.7231 IU/mL, resp., which showed no significant difference (P > 0.05). Conclusion Domestic freeze-dried HDCV for human use induced mild adverse reactions and showed good immunogenicity.