Introduction: Preptin is a recently isolated peptide hormone that is co-secreted with insulin from the pancreatic beta-cells. The aim of this study was to compare the effects of aerobic exercise and caloric restriction on serum preptin levels and HOMA-IR in sedentary obese women. Materials and methods: Forty women who referred to home health centers were divided into four groups for 16 weeks of follow up: Aerobic exercise (experimental group 1), caloric restriction (experimental group 2), aerobic exercise with caloric restriction (experimental group 3) and the control group. Training programs in experimental group 1 consisted of aerobic training and running on a treadmill for 105.183±5.63 minutes, 4 times a wk. In experimental group 2, subjects followed a diet with caloric restriction equivalent to physical activity energy expenditure. Subjects in the experimental group 3 used a training program similar to experimental group 1 for 66.85±5.34 minutes, 3 times a wk and received a diet with half the amount of caloric restriction of experimental group 2. Results: Weight, BMI and WHR showed significant reduction in the experimental groups. Serum preptin levels were decreased by 21.97%, 28.32% and 27.11% in experimental groups 1, 2 and 3 respectively. HOMA-IR was decreased significantly in the 3 groups. Significant correlations were seen between changes of preptin and changes of weight, WHR and HOMA-IR (p<0.05). Conclusion: Considering the relationship between preptin and insulin resistance and the influence of aerobic exercise and caloric restriction, preptin may play an effective role in weight management and prevention of diabetes.