Objective : To evaluate the safety and immunogenicity of a split-virion quadrivalent influenza vaccine. Methods : The healthy people aged three years or over in Wuyang County and Xiping County of Henan Province were divided into the experimental group, control group 1 and control group 2, and were vaccinated with split-virion quadrivalent influenza vaccines, split-virion trivalent influenza vaccines (without B/Victoria) and a split-virion trivalent influenza vaccines (without B/Yamagata) , respectively. The hemagglutination inhibition (HI) antibodies were detected before and after immunization. The incidence rate of adverse events following immunization (AEFI) , HI antibody positive conversion rate, the protection rate of HI antibodies and the growth of geometric mean titer (GMT) were calculated and compared with the standard of Food and Drug Administration (FDA). Results: Totally 2 924 people were recruited, with 975 in the experimental group, 974 in the control group 1 and 975 in control group 2. The incidence rate of AEFI in the experimental group was 11.7%, higher than 7.9% in control group 1 and 8.8% in control group 2 (P < 0.05) during 30 minutes and 8 days after inoculation. The positive conversion rates of HI antibodies of H1N1, H3N2, By and Bv in the experimental group were 78.5%, 53.3%, 78.3% and 62.9%, respectively. The rate differences of the positive conversion rates of HI antibodies of By between the experimental group and control group 2, and of Bv between the experimental group and control group 1 were 42.1% (95%CI: 38.0%-46.2%) and 33.2% (95%CI: 28.9%-37.5%) , with both lower limits of 95%CI more than -0.10. The GMT increase of HI antibodies was more than 2.5 times in the three groups. The protective rates of HI antibodies of H1N1, H3N2, By and Bv in the experimental group were 87.7%, 98.7%, 93.6% and 77.2%, respectively. The protective rates of HI antibodies of By in control group 2 and Bv in control group 1 were 71.1% and 51.0%, both lower than those in the experimental group (P < 0.05). Conclusions After the inoculation of the quadrivalent influenza vaccine, the positive conversion rates (>40%) , protection rates (>70%) and GMT increase (>2.5 times) of HI antibodies of H1N1, H3N2, By and Bv all meet the quality standards of FDA. The safety and immunogenicity of the quadrivalent influenza vaccine are not inferior to those of the trivalent influenza vaccine.