Tuberculosis (TB) causes significant morbidity and mortality on a global scale. The African region has 24% of the world's TB cases. TB overlaps with other infectious diseases such as malaria and HIV, which are also highly prevalent in the African region. TB is a leading cause of death among HIV-positive patients and co-infection with HIV and TB has been described as a syndemic. In view of the overlapping epidemiology of these diseases, it is important to understand the dynamics of the immune response to TB in the context of co-infection. We investigated the cytokine response to purified protein derivative (PPD) in peripheral blood mononuclear cells from TB patients co-infected with HIV or malaria and compared it to that of malaria- and HIV-free TB patients. A total of 231 subjects were recruited for this study and classified into six groups; untreated TB-positive, TB positive subjects on TB drugs, TB- and HIV-positive, TB- and malaria-positive, latent TB and apparently healthy control subjects. Our results demonstrate maintenance of interferon (IFN)-γ production in HIV and malaria co-infected TB patients in spite of lower CD4 counts in the HIV-infected cohort. Malaria co-infection caused an increase in the production of the T helper type 2 (Th2)-associated cytokine interleukin (IL)-4 and the anti-inflammatory cytokine IL-10 in PPD-stimulated cultures. These results suggest that malaria co-infection diverts immune response against M. tuberculosis towards a Th-2/anti-inflammatory response which might have important consequences for disease progression.