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Abstract Background Vaccination is important in influenza prevention but the immune response wanes with age. The circadian nature of the immune system suggests that adjusting the time of vaccination may provide an opportunity to improve immunogenicity. Our previous cluster trial in Birmingham suggested differences between morning and afternoon vaccination for some strains in the influenza vaccine in older adults. Whether this effect is also seen in a younger age group with less likelihood of compromised immunity is unknown. We therefore conducted an individual-based randomized controlled trial in Guangzhou to test the hypothesis that influenza vaccination in the morning induces a stronger immune response in older adults than afternoon vaccination. We included adults in middle age to determine if the effect was also seen in younger age groups. Results Of the 418 participants randomised, 389 (93.1%, 191 middle-aged adults aged 50–60 years and 198 older adults aged 65–75 years) were followed up. Overall, there was no significant difference between the antibody titers (geometric mean /95% CI) after morning vs afternoon vaccination (A/H1N1: 39.9 (32.4, 49.1) vs. 33.0 (26.7, 40.7), p = 0.178; A/H3N2: 92.2 (82.8, 102.7) vs. 82.0 (73.8, 91.2), p = 0.091; B: 15.8 (13.9, 17.9) vs. 14.4 (12.8, 16.3), p = 0.092), respectively. However, in pre-specified subgroup analyses, post-vaccination titers for morning versus afternoon vaccination in the 65–75 years subgroup were (A/H1N1): 49.5 (36.7, 66.6) vs. 32.9 (24.7, 43.9), p = 0.050; (A/H3N2): 93.5 (80.6, 108.5) vs. 73.1 (62.9, 84.9), p = 0.021; (B): 16.6 (13.8, 20.1) vs. 14.4 (12.3, 17.0), p = 0.095, respectively. Among females, antibody titers for morning versus afternoon vaccination were (A/H1N1): 46.9 (35.6, 61.8) vs. 31.1 (23.8, 40.7), p = 0.030; (A/H3N2): 96.0 (83.5, 110.3) vs. 84.7 (74.4, 96.5), p = 0.176; (B): 14.8 (12.7, 17.3) vs. 13.0 (11.3, 14.9), p = 0.061, respectively. In the 50–60 years old subgroup and males, there were no significant differences between morning and afternoon vaccination. Conclusions Morning vaccination may enhance the immunogenicity to influenza vaccine in adults aged over 65 and women. An intervention to modify vaccination programs to vaccinate older individuals in the morning is simple, cost free and feasible in most health systems.