Recurrent erythema multiforme is a rare disorder, clinically characterized by symmetrically distributed, erythematous, and bullous skin and mucous lesions, mainly precipitated by a preceding herpes simplex infection. In rare cases, EM presents continuous or persistent relapses, and has been related to an Epstein-Barr virus infection. We report 2 cases of severe, persistent erythema multiforme, treated with thalidomide, with complete disease suppression in both cases. Thalidomide induces immunomodulator, anti-inflammatory, and anti-angiogenic effects, and may be considered as the elective treatment of this rare variety of erythema multiforme. However, in order to avoid neuropathic side effects, patients under thalidomide therapy should be monitored every 6 months with nerve conduction studies while taking the drug.