Background: Melasma is an acquired therapeutically problematicdisease characterized by symmetrical facial hypermelanosis. Theaim of this study was to evaluate the efficacy of azelaic acid20% cream in the treatment of melasma in Iranian patients andcompare it with hydroquinone 4% cream which has been thestandard treatment.Method: The study was an open clinical trial with a split-facedesign. All patients applied hydroquinone 4% cream on theright side and azelaic acid 20% cream on the left side for 20weeks. Modified melasma area and severity index (mMASI) wasdetermined for each patient at the beginning and at the end ofstudy and compared statistically.Result: Thirty-three patients were included in the study. Althoughboth medications were effective in reducing mMASI, there wasno statistical difference between the two (P value=0.6). Overall,69.7% of the patients on the hydroquinone 4% side and 63.6%on the azelaic acid 20% side showed good to excellent response.The subjective patient assessment of improvement was 75.7% forhydroquinone 4% and 66.6% for azelaic acid 20%.Conclusion: Both topical hydroquinone 4% and topical azelaicacid 20% had almost similar effects. Considering the relativelyless known side effects of azelaic acid compared to hydroquinone,it can be an appropriate substitute in the treatment of melasma.