Recurrent erythema multiforme (REM) may have frequent episodes over a period of several years and is considered to be a hypersensitivity reaction associated with infection or medication. REM is a mucocutaneous disorder which is characterized by targetoid lesions. Most of the cases are caused by herpes simplex virus infection. Systemic corticosteroid is frequently used to treat REM due to its effects in suppressing the disease. When REM is unresponsive to systemic corticosteroid, steroid-sparing treatment needs to be instituted. We reported a case of REM in a 49-year-old male. There were complaints of burning sensations on the skin lesions, along with swelling on both hands. On physical examination, erythematous macules and targetoid lesions were found on both palms, arms, and legs. During hospitalization, dexamethasone 20 mg was administered in a tapering dose but new skin lesions still appeared. Two days after azathioprine 50 mg twice daily was added to the treatment, skin lesions and swelling on the patient's hands were diminished and the burning sensation disappeared. No side effects of azathioprine were found in this patient and no recurrence until two weeks after hospitalization. This case report demonstrated the efficacy of combined treatment of dexamethasone and azathioprine for REM cases unresponsive to systemic corticosteroid.