OBJECTIVES: The purpose of this study was to compare the effects of pioglitazone and linagliptin on glycemic control, lipid profile and high-sensitivity C-reactive protein (hs-CRP) parameters in patients with type 2 diabetes treated with metformin. METHODS: The present randomized clinical trial was conducted on 60 patients with type 2 diabetes treated with metformin in the age range of 30-60 years. The participants with informed consent were randomly assigned to receive pioglitazone or linagliptin. The first intervention group (n=30) received 30 mg of pioglitazone daily and the second intervention group (n=30) received 5 mg of linagliptin daily for 12 weeks. Fasting blood samples were taken from patients at the baseline and after 12 weeks to measure related variables. The current study was approved in Kashan University of Medical Sciences (with the code of ethics of IR.KAUMS.MEDNT.REC.1398.016), and the Iranian Registry of Clinical Trials (with the registration number of IRCT20170513033941N66). RESULTS: The linagliptin administration significantly reduced serum levels of fasting blood sugar (p=0.03), blood sugar 2 h after a meal (p=0.02), glycosylated hemoglobin (p=0.02) and hs-CRP (p=0.005) after 12 weeks compared with pioglitazone. In contrast, the pioglitazone administration significantly decreased triglyceride levels (p=0.01) and increased HDL-cholesterol (p=0.002) compared to linagliptin. In addition, the administration of both linagliptin and pioglitazone drugs had no significant effect on LDL-cholesterol, total cholesterol, systolic and diastolic blood pressure, creatinine and blood urea. CONCLUSIONS: The present study demonstrated the superiority of linagliptin over pioglitazone for glycemic control, although pioglitazone compared to linagliptin showed greater efficacy in reducing triglycerides and raising HDL-cholesterol.