Free fatty acids deposition in non-adipose tissues such as the heart is a characteristic of insulin resistant states which features hyperinsulinemia and dipeptidyl peptidase-4 (DPP-4) activation. Estrogen-progestin oral contraceptives (OC) treatment reportedly increased DPP-4 activity in rat tissue and DPP-4 inhibitors have anti-diabetic and anti-inflammatory properties. This study aims to investigate the effects of DPP-4 inhibition on cardiac free fatty acid (FFA) deposition in estrogen-progestin treated female rats.From our data, estrogen-progestin OC exposure in female rats led to elevated plasma insulin, cardiac DPP-4 activity, FFA and triglyceride (TG) accumulation, Triglyceride/high density lipoprotein (TG/HDL) ratio, adenosine deaminase/xanthine oxidase/uric acid pathway, lipid peroxidation, glycogen synthase activity and alanine phosphatase whereas cardiac glucose-6-phosphate dehydrogenase, Na/K-ATPase and nitric oxide (NO) were decreased. However, DPP-4 inhibition resulted in decreased plasma insulin, cardiac DPP-4 activity, FFA, TG and TG/HDL-C ratio and alkaline phosphatase. These were accompanied by reduced adenosine deaminase/xanthine oxidase/uric acid (ADA/XO/UA) pathway, lipid peroxidation and augmented NO and Na/K-ATPase in estrogen-progestin OC-treated rats.DPP-4 inhibition attenuated cardiac lipid deposition accompanied by reduced activity in the ADA/XO/UA pathway in estrogen-progestin OC-treated female rats. DPP-4 is therefore a plausible therapeutic target in cardiometabolic disorders