Background Leptin is an adipose tissue-derived hormone shown to be involved in pathophysiological mechanisms related to diabetes. Few studies examined the association between plasma leptin and diabetes mellitus in humans. Therefore, we examined the association between plasma leptin levels and diabetes in a Sudanese diabetic patient's compared with a healthy subjects regarded by different parameters. Methods: We examined the 1272 participants 20 -70 years of age, 872 diabetic patients and 400 control healthy subjects, in different hospitals in (Khartoum-Sudan) during the period 1/4/2012 to 1/9/2012. Plasma leptin levels, total cholesterol were determined categorized by BMI, sex and smoking habits in all study subjects. Results: There were significant associations between plasma leptin levels and diabetes mellitus after adjusting for BMI, smoking and serum cholesterol level (P value < 0.01). But there were insignificant association between plasma leptin levels and diabetes mellitus after adjusting of both men and women. Conclusion: Plasma leptin levels are independently associated with diabetes mellitus after adjustment for BMI, total cholesterol and smoking.