Melasma is an acquired hyperpigmentation skin disorder in sun-exposed areas. It occurs almost exclusively over the face, and is most commonly seen in women. Several depigmenting agents have been used for the treatment of melasma among which hydroquinone has been the most widely used due to its efficacy and safety in short-term use. However, hydroquinone is recently reported to be a cytotoxic and mutagenic compound in mammalian cells and is thus banned in several countries. Hydroquinone ban has caused investigators to search for alternative depigmenting agents for the treatment of melasma in recent years. Methimazole is an antithyroid agent orally used in humans since several decades and has been shown that when applied topically, it inhibits melanin synthesis and causes skin depigmentation in lab animals as well as human subjects. Herein, we report two hydroquinone-resistant melasma patients who were successfully treated with methimazole cream. Application of 5% methimazole cream once daily resulted in significant improvement of melasma in both patients after 8 weeks. The efficacy of methimazole for melasma treatment as well as its advantages over other known depigmenting compounds (non-mutagenicity, non-cytotoxicity and high tolerability profile) suggests that topical methimazole should be added to the armamentarium of anti-melasma treatment.