We investigated the serum paraoxonase (PON) activity and genotype distribution in 139 patients with non-insulin-dependent diabetes mellitus and in 240 control subjects in a Japanese population. There were no significant differences in PON genotype frequencies between the diabetic and control subjects, but the PON activity was significantly less in diabetic subjects (p<0.01). PON activity was significantly related to levels of total cholesterol and high density lipoprotein (HDL) cholesterol in the control subjects, but not in the diabetic subjects. In diabetic subjects with the genotype AA, the mean maximum intimal-medial thickness (IMT) of the carotid artery was significantly greater than in subjects with genotype AB or BB. PON may play an important role in the development of atherosclerosis associated with diabetes mellitus.