Type 2 diabetes mellitus (T2D) is currently one of the fastest growing noncommunicable diseases in the world. It is induced by the pathogenic interaction between insulin resistance and secretion. This group of clinically heterogeneous disorders currently affects approximately 4% of the general population, but it is rapidly increasing, especially in developing regions such as sub-Saharan Africa. During this investigation, a diabetic (n = 227) and control cohort (n = 226) of adult black South African individuals were screened for the reported single nucleotide polymorphisms, termed C-11377G and G-11391A, within the promoter of the adiponectin (ACDC) gene. Genotyping was achieved via a real-time polymerase chain reaction method. It was determined that the variant allele at G-11391A as well as the 12 haplotype was significantly associated with a protective factor with regard to T2D susceptibility. The low frequency of this variant within the cohorts investigated indicated a minor role in decreasing disease susceptibility. It may not be a significant disease risk factor in itself, but may assist in elucidating the mechanism of disease susceptibility. When compared to various non-African populations, it becomes apparent that the investigated single nucleotide polymorphisms have differential effects depending on the population investigated. This investigation therefore underscores the genetic heterogeneity at T2D susceptibility loci within the black South African population.