The impact of Tuberculosis (TB) places an immense burden on the health care system. Infection with Human Immunodeficiency Virus (HIV) is a significant risk factor in the development and progression of TB disease. Single Nucleotide Polymorphisms (SNPs) in the promoter region of Interleukin-10 (IL-10) and Tumour Necrotic Factor-Alpha (TNF-α) may play a major role in the disease mechanism and understanding these mechanisms might prove to be a useful diagnostic tool in evaluating the immune regulation and progression of the disease. This study aimed to determine the relationship between cytokine levels and gene variants of Interleukin-10 and Tumour Necrotic Factor Alpha in TB and HIV-infected participants. Cytokine levels were determined by ELISA, and SNPs were determined by MassArray®. The levels of TNF-α were higher in the TB group than the HIV (p < 0.001) and TB-HIV (p = 0.011) groups, but similar to the TNF-α levels in the control group. In the HIV group, IL-10 levels were higher than those of the TB (p < 0.001) and control groups (p = 0.039), whereas there was no difference between the IL-10 levels in the HIV and the TB-HIV infection groups. The ratio was determined and there were no differences between the four infection groups. In this study, no associations were detected between the circulating plasma levels of TNF-α and IL-10 and their genotypes. Our data showed that the gene variants were not associated with circulating plasma levels of TNF-α and IL-10 in our study population. A pro-inflammatory environment was found in the TB and TB-HIV groups, which is suggesting of bacterial clearance, while an anti-inflammatory environment was found in the HIV group, which suggests the suppression of viral replication.