Non-insulin-dependent (type II) diabetes mellitus is associated with significant abnormalities of lipoprotein metabolism. Control of glycemia rarely completely corrects the alterations in lipid metabolism, suggesting a participation of environmental and genetic factors. The observation that tumor necrosis factor (TNF) can modulate triglyceride metabolism offers a new genetic candidate to be analyzed. Samples of DNA from 91 control subjects and 61 diet-treated type II diabetic patients were analyzed to determine the lipid profile and a possible association with TNF genetic polymorphisms. For TNF restriction fragment length polymorphisms, we used the Nco I restriction enzyme and a TNF-alpha probe obtaining two allelic bands at 10.5 and 5.5 kb. We found a significant association (P < .01) of the 10.5-kb homozygous genotype in type II diabetic subjects with high triglyceride levels. Furthermore, these patients showed significant differences in triglycerides as compared with matched control subjects with the same genotype (P < .001). This study provides support for considering the TNF locus as a susceptibility genetic region in the hypertriglyceridemia of type II diabetes.