Objective: To evaluate the immunogenicity and safety of co-administration with bivalent human papillomavirus (HPV) vaccine and hepatitis E virus (HEV) vaccine, so as to provide reference for optimizing the vaccination schedule. Methods: Females aged 18 to 25 years were recruited from September to October 2021 in Hengdian College of Film & Television in Zhejiang Province and randomly divided into the HPV+HEV group, the HPV group, and the HEV group. The vaccination procedures were one dose each at 0, 1, and 6 months. Immunogenicity was evaluated by detecting the geometric mean titers (GMT) of HPV16 IgG, HPV18 IgG, and/or HEV IgG antibodies before the first vaccination and one month after the full course of immunization, and comparing the difference in seroconversion, and the GMT ratio. The non-inferiority margin was set at a seroconversion difference of ≤5%, and the lower limit of the 95%CI of the GMT ratio was >0.5. Safety was evaluated by collecting conjunctive local reactions/events and systemic reactions/events within 7 days after each dose, non-conjunctive adverse events within 30 days after each dose, and serious adverse events throughout the observation period (0 to 7 months). Results: A total of 240 females were included, among whom 236 completed the full vaccination program, including 79 in the HPV+HEV group, 77 in the HPV group, and 80 in the HEV group. One month after the full course of immunization, the seroconversion rates of HPV16 IgG and HPV18 IgG antibodies in both the HPV+HEV group and the HPV group were 100%, and the differences in seroconversion rates were 0 (95%CI: -3.39%-+∞). The seroconversion rates of HEV IgG antibodies in both the HPV+HEV group and the HEV group were 100%, and the difference in seroconversion rates was 0 (95%CI: -3.27%-+∞). The GMT of HPV16 IgG and HPV18 IgG antibodies in the HPV+HEV group was 393.88 and 284.86 IU/mL respectively, which was not inferior to 489.39 and 341.24 IU/mL in the HPV group, and the GMT ratios were 0.80 (95%CI: 0.66-+∞) and 0.83 (95%CI: 0.68-+∞), respectively. The GMT of HEV IgG in the HPV+HEV group was 13.55 U/mL, which was not inferior to 12.72 U/mL in the HEV group, and the GMT ratio was 1.07 (95%CI: 0.92-+∞). The incidences of pain, pruritus, and induration in the HPV+HEV group were 54.43%, 21.52% and 40.51% respectively, which were significantly higher than 10.39%, 0, and 0 in the HPV group (all P<0.05). The incidences of redness/swelling, muscle pain/general weakness in the HPV+HEV group were 2.53% and 0, respectively, which were significantly lower than 12.50% and 16.25% in the HEV group (both P<0.05). Conclusion The co-administration of the bivalent HPV vaccine and HEV vaccine is not inferior to individual vaccination in terms of immunogenicity and safety, and the vaccination plan can be optimized through co-administration.