Background: 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 different cytokines. These changes in cytokine levels can affect the immune function, and have the potential to directly impact on the course of HIV disease. This study seeks to give an insight into the role of cytokines in the establishment and maintenance of effective immunologic control of HIV replication during the chronic infection stage. The knowledge generated will assist in the development of effective vaccines and therapeutic strategies aimed at slowing the rate of HIV disease progression including cytokine-based therapy. Objective: To characterize longitudinal changes in plasma cytokine concentration in HIV-1C chronically infected, ART naïve participants and to establish their influence on disease progression and viraemia. Design and methods: Plasma levels of IL-1α, IL-7, IL-12p40, GM-CSF and IFN-γ were quantified in samples from 60 treatment naïve subjects selected from the placebo arm of the Micronutrient study at Botswana Harvard AIDS Institute Partnership. The Micronutrient Study examined the role of multivitamins and selenium supplementation in HIV-1 disease progression. Participants were stratified into progressors and non-progressors based on their rates of CD4+ T cell depletion during the study period. Cytokines levels were compared between progressors and non-progressors 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. Results: IL-12p40 levels were significantly higher in the progressors than in non-progressors at enrolment and 24 months (P < 0.05), but not significantly different at 12 months (P=0.1276). Levels of IL-1α, IL-7, IFN-γ and GM-CSF did not differ significantly among the two groups. Except for IL-12p40 which displayed an inverse correlation with CD4+ T lymphocyte cell counts and a direct correlation with viral load, all other cytokines showed no correlations. Conclusion: Among the cytokines examined, IL-12p40 was found to be 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 with moderate degree of immunodeficiency as in our study, CD4+ 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