Objectives: This study aimed to investigate the association of demographic and clinical characteristics, including HIV-specific parameters with the antibody response to a third dose of a SARS-CoV-2 mRNA vaccine in people living with HIV-1 (PWH). Design: Post-hoc analysis of data collected during the observational extension of the COrona VaccinE tRiAL pLatform trial (COVERALL-2) nested into the Swiss HIV Cohort Study. Methods: Serological measurements were conducted on a total of 439 PWH who had received a third dose of either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) SARS-CoV-2 vaccine. Antibody reactivity was assessed using the multifactorial ABCORA immunoassay that defines SARS-CoV-2 seroconversion and predicts neutralization activity. The association between log transformed antibody reactivity and various baseline factors, including vaccine type, demographics, immune and viral status, smoking status, co-morbidities, infection history, and co-medication with chemotherapy and immunosuppressive drugs, was investigated using a multivariable linear regression model. Results: Antibody response against SARS-CoV-2 after a third vaccination was significantly lower among PWH with CD4 cell count <350 cells/μl (ratio of means (RM) 0.79; 95% confidence interval (CI) 0.65–0.95). Having a detectable HIV-1 viral load ≥50 copies/ml and being on concurrent chemotherapy was associated with an overall lower humoral immune response (RM 0.75; 95% CI 0.57–1.00 and 0.34; 95% CI 0.22–0.52, respectively). Conclusions: The study highlights the importance of optimal antiretroviral treatment (ART) for PWH, emphasizing the need for timely intervention to enhance the vaccine immunogenicity in this population. Moreover, it underscores the significance of sequential mRNA vaccination and provides important evidence for informing vaccine guidelines.