To evaluate the safety and immune effect of recombinant hepatitis B vaccine (CpG ODN adjuvant). On Oct. 26, 2016, we launched volunteer recruitment in Kaihua county, Quzhou city, Zhejiang Province. In the randomized, double-blind, controlled trial, a total of 48 subjects with negative HBV screening tests and normal hepatorenal function among 18 and 60 years old were selected and divided into two groups randomly, 24 cases each. The experimental group was given 250 μg of CpG ODN recombinant (Hansenula polymorpha) Hepatitis B vaccine and the control group was given 10 μg of commercial Hepatitis B vaccine with timed at 0, 1and 6 months. The inoculation reactions were compared the difference between the two groups after observed and recorded in time periods. We also collected serum before and after immunization to compare the two groups of anti-HBs positive rate, geometric mean concentration(GMC). During the study period, the incidence of adverse events was 66.67%(16/24) in the experimental group and 54.17%(13/24) in the control group, with no significant difference(=0.556). The severities of adverse events were level 1 or level 2, and no level 3 or above adverse reactions occurred. After full-course immunization, in the FAS data set, the anti-HBs GMC in the experimental group [2 598.56(1 127.90-5 986.90) mIU/ml] was higher than that in the control group[371.97(164.54-840.91) mIU/ml] In the PPS set, the GMC of test group was 7 808.21(3 377.00-18 052.00) mIU/ml, which was higher than that of the control group [843.22(213.80-3 325.90) mIU/ml]. The anti-HBs positive rate of FAS(PPS) was 95.83%(100.00%) in the experimental group and the control group; The anti-HBs strongly positive rate of FAS(PPS) was 79.17%(90.00%) in the experimental group and 33.33%(50.00%) in the control group, with statistically significant differences among the FAS set(=0.003) and no statistically significance differences among the PPS set(=0.074). CpG Hepatitis B Vaccine is safe and shows better immunogenicity than the control vaccine.