The increasing worldwide prevalence of type 2 diabetes mellitus (T2D) is a serious global health concern. Although T2D has a strong genetic etiology, limited knowledge exists about the common variants associated with it in the black South African population. This study set out to evaluate the association of previously reported common variants in other world populations with T2D susceptibility in a black South African population of Setswana descent. A case-control study design of 178 cases and 178 controls nested in the Prospective Urban Rural Epidemiology (PURE) study was conducted wherein we genotyped for 77 single nucleotide polymorphisms (SNPs). PLINK software was used to evaluate the standard genetic models of disease penetrance for the association of the common variants with impaired glucose tolerance (IGT) while adjusting for age, sex, and body mass index. Only rs1436955 significantly associated with an increase in T2D risk; three other variants, rs831571, rs8050136, and rs7542900, significantly associated with decreased risk of T2D. However, none of the four SNPs had significant associations after correcting for multiple testing (p < 0.05). Although further studies are required to confirm these observations, the common variants associated with T2D risk among the Black South Africans of Setswana descent might likely be different than those in the Asian and European populations. This study supports the broader thesis that the genetic background of Africans is diverse and cannot be directly extrapolated using genetic variants from other ethnicities. Therefore there is a need to identify the population-specific variants linked with T2D in Africa.