Statement of the Problem: Elevated serum levels of inflammatorymediators reflect low-grade chronic inflammation and havebeen attributed to be associated with insulin-resistant states.Therefore, insulin-lowering agents have been recommendedto improve both reproductive and metabolic aspects of PCOS.This study aimed to compare metformin and combination ofmetformin plus pioglitazone on menstrual cyclicity, hormonalparameters, insulin resistance and inflammatory biomarkersin women with PCOS. Methodology & Theoretical Orientation:One hundred and six women with PCOS participatedin the study. All subjects were randomized in to two-arm interventions.Arm-1: metformin 500 mg (BD) daily. Arm-2: Combined(metformin 500 mg BD and pioglitazone 15 mg BD) for12 weeks. The primary outcome measure was serum level ofIL-6 and IL-8 using ELISA assay. Secondary outcome was insulinresistance; assessed using HOMA-IR. Findings: At baselinewomen with PCOS had significantly elevated circulating concentrationsof IL-6 and IL-8. Treatment decreased IL-6 in bothgroups, however only the combination group (p= 0.005) had asignificant decrease. IL-8 had a significant decrease after treatmentin both groups (p= <0.001). HOMA-IR and insulin levelsalso decreased in both groups (both p= <0.001). Testosterone,FSH and prolactin significantly decreased in both groups. LHalso decreased in both groups, however, the change was significantonly in the combination group (p=0.013). Both treatmentgroups were associated with the reduction in menstrual irregularities,sizes of ovaries and number of follicles. Significance:Combination of metformin and pioglitazone therapy was moreeffective compared to metformin alone in reducing the levelsof IL-6 and IL-8 as well as insulin resistance in PCOS. Theaddition of pioglitazone with metformin had an additionaleffect on decreasing inflammation and normalizing hormonalimbalance. Thus modified treatment protocols of combinationtherapy could further improve the outcome.