Chromosome 17 is known to contain TB susceptibility genes. Polymorphisms in two of these genes, namely NOS2A and CCL2, have been associated with TB in various populations. To investigate a possible association of gene variants with TB in the South African Coloured population we genotyped SNPs from NOS2A and CCL2 in over 800 TB cases and controls. We found a significant association between TB and two haplotypes, containing the functional rs9282799 and rs8078340 SNPs, in the NOS2A promoter. The T allele of rs8078340, found in the haplotype over-represented in cases (p=0.015, p_c=0.038, OR=1.4, 95% CI [1.1–1.8]), was previously shown to decrease the quantity of DNA-protein complex bound as well as the duration of binding and may decrease nitric oxide (NO) production. The C allele of rs8078340 was present in the haplotype more frequent in controls (p=0.011, p_c=0.029, OR=1.4, 95% CI [1.1–1.8]). In the single-point analysis of NOS2A, rs2779249 (previously associated with TB in Brazilians) and the functional rs8078340 were nominally associated with disease. No association was found between any of the other SNPs or haplotypes studied and TB. This study presents evidence that haplotypes in the NOS2A promoter influence susceptibility to TB and confirms the importance of NO production in the disease.