There are data to suggest that both the humoral and cellular immune responses directed against Tat are beneficial in delaying HIV disease progression. We examined the association between the occurrence of Tat-specific binding antibodies (Abs) and different parameters of HIV-1 disease progression. We generated eight Tat proteins, derived from HIV-1 subtypes A, B, C, and D, and circulating recombinant form CRF01_AE. These proteins were used to screen for Tat-specific binding Abs by an ELISA. Using five Tat proteins, we investigated whether the occurrence of Tat-specific Abs within 2 years after seroconversion for the majority, affected disease progression over time among 126 participants using survival analysis and rate of CD4 decline. Of these, 52 participants with a sample at 1.5 and 4.5 years after seroconversion were further examined to study the effect of Tat-specific Ab loss or maintenance on disease progression. Finally, using all the eight Tat proteins, we also investigated whether specific Abs to these Tat proteins among 48 participants, grouped as rapid progressors (RP, n = 26) and long-term survivors (LTS, n = 22) according to their CD4 decline over time, affected disease progression. Survival analysis did not reveal any evidence of protection from progression by Tat-specific Abs. Comparison of rate of CD4 declines between individuals with and without Abs to any Tat protein showed only a small and borderline significant advantage of having Tat-specific Abs (p = 0.043). There was no correlation between either loss or maintenance of Tat-specific Abs and disease progression. Comparison of LTS with RP showed no evidence that Tat-specific Abs slows participants' disease progression. This study showed no evidence of a protective effect of having Tat-specific Abs among these Ugandan subjects.