BACKGROUND/OBJECTIVES: This study explored interactions between dietary fat intake and the tumor necrosis factor-a gene (TNFA) -238 G4A polymorphism (rs361525) on adiposity and serum lipid concentrations in apparently healthy premenopausal black and white South African (SA) women. SUBJECTS/METHODS: Normal-weight (N ¼ 107) and obese (N ¼ 120) black, and normal-weight (N ¼ 89) and obese (N ¼ 62) white SA women underwent measurements of body composition, fasting lipids and dietary intake, and were genotyped for the -238 G4A polymorphism. RESULTS: Black women had a higher -238 GA genotype frequency than white women (Po0.001), but there were no differences between body mass index groups. Black women with the -238 A allele had a greater body fat % than those with the GG genotype (Po0.001). Further, in black women, with increasing polyunsaturated:saturated fat ratio and omega-6 (n-6):omega-3 (n-3) ratio, high-density lipoprotein-cholesterol (HDL-C) concentrations decreased, and total cholesterol (T-C):HDL-C ratio increased in those with the GA genotype but not the GG genotype. In addition, with increasing n-3 polyunsaturated fatty acid intake (percentage of total energy intake, %E), T-C:HDL-C ratio decreased in those with the GA genotype, but not in those with the GG genotype. In white SA women, with increasing eicosapentaenoic acid (%E) intake, low-density lipoprotein-cholesterol concentrations decreased in those with the GG genotype but not the GA genotype. CONCLUSIONS: The -238 G4A polymorphism was associated with body fatness in black women. Interactions between -238 G4A genotypes and dietary fat intake on serum lipids and adiposity differed depending on dietary fat intake, but those for serum lipids were not the same in black and white SA women.