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. These changes in cytokine levels can affect the immune function, and have the potential to directly impact the course of HIV disease. We characterized plasma cytokine concentration profiles in HIV-1 subtype C chronically infected, antiretroviral therapy (ART)-naive participants to establish their influence on disease progression and viremia. Plasma levels of interleukin (IL)-1α, IL-7, IL-12p40, granulocyte macrophage-colony-stimulating factor (GM-CSF), and interferon (IFN)-γ were quantified in samples from 60 treatment-naive participants in the placebo arm of the completed Micronutrient-HIV disease progressions study, "Dikotlana" (2004-2009) in Gaborone, Botswana. Participants were stratified into progressors (P) and nonprogressors (NP) based on their rates of CD4(+) T cell depletion during the study period. Nonprogressors were those who had <1% CD4(+) T cell depletion at 24 months postenrollment. Progressors were defined as those with CD4(+) T cell depletion of >15% at 24 months postenrollment. Cytokine levels were compared between P and NP using the 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 nonprogressors and progressors, respectively. Nonprogressors had a higher viral set point than progressors. IL-12p40 levels were significantly higher in the P than in NP at enrollment and 24 months (p < 0.05). Levels of IL-1α, IL-7, IFN-γ, and GM-CSF did not differ significantly between the two groups. Except for IL-12p40, which displayed an inverse correlation with CD4(+) T cell counts and a direct correlation with viral load, all other cytokines showed no correlations. 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.