The concerns exist regarding the inadequate immune response to inactivated COVID-19 vaccines in some people living with HIV (PLWH). A prospective cohort study was conducted across four regions of Zhejiang, China. Both PLWH and healthy controls (HCs) received two doses of the inactivated COVID-19 vaccine. Adverse reactions within 7 days after each injection were monitored. PLWH with CD4 counts <500 cells/µL received a third dose. Neutralizing antibodies (NAbs) and IgG were measured to evaluate the immunogenicity of each dose. A total of 400 PLWH were enrolled, with 12.2% aged ≥60 years. Adverse reactions to the first two doses were mild or moderate in PLWH (12.0% and 5.5%). After the second dose, the geometric mean titer (GMT) of NAbs was lower in PLWH (46.9, 95% confidence interval [CI] 43.6-50.4) compared to HCs (58.2, 95% CI 53.4-63.5). However, seropositivity rates were similar (97.9% vs 100.0%). Single and multifactor generalized estimating equation analysis revealed that PLWH aged ≥60 years with CD4 count <500 cells/µL exhibited a weaker immune response. After a third dose in this subgroup (aged ≥60 years), the GMT of NAbs was 61.5 (95% CI 47.8-79.2), significantly lower than the 18-59 years group. In conclusion, PLWH showed a weaker and delayed immune response after receiving two doses of the inactivated COVID-19 vaccine. Older age combined with a lower CD4+ T cell count posed significant challenges to achieving an adequate immune response. Strategies to improve COVID-19 vaccine uptake and overall immunization in PLWH are needed.IMPORTANCEIn this prospective cohort study, we analyzed the safety and immunogenicity of a two-dose schedule of the inactivated COVID-19 vaccine (Covilo) in people living with HIV (PLWH). We also investigated factors associated with antibody titers and seropositivity rates. Additionally, we evaluated the immunogenicity of an inactivated COVID-19 vaccine booster in PLWH with CD4+ T cell counts ≤500 cells/µL within both 18-59 and ≥60 years age groups. We found vaccination with the inactivated COVID-19 vaccine was well-tolerated in PLWH but induced a weaker and delayed immune response compared with healthy controls. Importantly, the older PLWH with low CD4+ T cell counts face considerable challenges in mounting an adequate immune response to vaccines, even after booster immunization. Our findings highlight the need for strategies to improve vaccine immunogenicity in PLWH with low immune responses, particularly among older individuals and those with low CD4+ T cell counts.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05075070.