HIV infects cells of the immune system causing immune activation and proliferation of immune cells, leading to alteration of production and activity of a number of cytokines. We characterized plasma cytokine concentration profiles in HIV-1 subtype C chronically infected, ART naïve participants to establish their influence on disease progression and viraemia. Plasma levels of IL-1α, IL-7, IL-12p40, GM-CSF and IFN-γ were quantified in samples from 60 treatment naïve participants in the placebo arm of the completed Micronutrient-HIV disease progressions study in Botswana. Participants were stratified into progressors (P) and non-progressors (NP) based on their rates of CD4+ T-cell depletion during the study period. Non-progressors were those that had <1% CD4+ T-cell depletion at 24-months post enrolment. Progressors were defined as those with CD4+ T-cell depletion of >15% at 24 months post enrolment. Cytokine levels were compared between P and NP using Mann-Whitney U-test. Logistic regression analysis was used to determine if cytokines predicted disease progression. Correlations of cytokines with CD4+ T-cell counts and viral loads were determined by the Spearman rank test. Median baseline CD4+ T-cell counts were 453 (Q1,Q3 401,592) and 479 (Q1,Q3 401 – 592) for non-progressors and progressors, respectively. Non-progressors had a higher viral se-t point than non-progressors. IL-12p40 levels were significantly higher in the P than in NP at enrolment and 24 months (p < 0.05). IL-12p40 levels also displayed an inverse correlation with CD4+ T -cell counts and a direct correlation with viral load. IL-12p40 was found to be the most significant predictor of progression and its production was most likely driven by HIV replication products as evidenced by its direct correlation with viral load. In chronic HIV-1 subtype C infection, CD4+ T-cell counts and plasma cytokine levels may not necessarily evolve in parallel, suggesting the involvement of other factors in determining the rates of CD4+ T-cell depletion.