| Summary: | <jats:p>South Africa has the highest prevalence of HIV and tuberculosis (TB) co-infection globally. Recurrent TB, caused by relapse or reinfection, makes up the majority of TB cases in South Africa, and HIV infected individuals have a greater likelihood of developing recurrent TB. Given that TB remains a leading cause of death for HIV infected individuals, and correlates of TB recurrence protection/risk have yet to be defined, here we sought to understand the antibody associated mechanisms of recurrent TB by investigating the humoral response in a longitudinal cohort of HIV co-infected individuals previously treated for TB with and without recurrent disease during follow-up, in order to identify antibody correlates of protection between individuals who do not have recurrent TB and individuals who do. We used a high-throughput, “systems serology” approach to profile biophysical and functional characteristics of antibodies targeting antigens from <jats:italic>Mycobacterium tuberculosis (Mtb)</jats:italic>. Differences in antibody profiles were noted between individuals with and without recurrent TB, albeit these differences were largely observed close to the time of re-diagnosis. Individuals with recurrent TB had decreased <jats:italic>Mtb</jats:italic>-antigen specific IgG3 titers, but not other IgG subclasses or IgA, compared to control individuals. These data point to a potential role for <jats:italic>Mtb</jats:italic>-specific IgG3 responses as biomarkers or direct mediators of protective immunity against <jats:italic>Mtb</jats:italic> recurrence.</jats:p>
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