Objective:To determine plasma cytokine levels [tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6] in African patients infected with HIV-2 relative to values in HIV-1-infected patients, and their relation to immunologic and clinical status.Design:Questions about the observed differences in the pathogenesis of HIV-2 and HIV-1 remain unanswered. Cytokines, especially TNF-α, are involved in the regulation of HIV-1 replication, and can be found in the plasma of HIV-1 -infected individuals. Therefore, we evaluated TNF-α, IL-1β and IL-6 levels in the plasma of African patients with different stages of HIV-2 disease. This was a 3-year prospective follow-up study.Methods:Cytokine plasma levels were assayed in 40 HIV-2− and 51 HIV-1 -infected patients from Africa. Nineteen of the 40 HIV-2-infected-patients underwent serial assays every 4 months for 3 years. Data were analysed in relation to the number of CD4+ and CD8+ cells, viral load and clinical status.Results:Plasma levels of TNF-α and IL-1β were significantly higher in all the HIV-1− and HIV-2-infected patients than in healthy controls; IL-6 levels were around the detection limit for all patients. TNF-α levels were lower in the HIV-2-infected than in the HIV-1-infected patients at all Centers for Disease Control and Prevention (CDC) disease stages, including the asymptomatic phase. The CD4+ cell count was always higher in the HIV-2-infected patients, regardless of CDC stage. The prospective follow-up showed that TNF-α levels remained stable during the course of HIV-2 disease, as did the CD4+ cell count and virus load.Conclusion:Lower and stable plasma TNF-a levels in African patients infected with HIV-2, associated with lower viral load and higher CD4+ cell count, suggests the existence of a more appropriate and efficient immune response to HIV-2 than to HIV-1.