Abstract: Clinicians are frequently confronted with patients presenting with oral aphthous ulcers or orogenital aphthae. Patients with complex aphthosis are characterized by the nearly constant presence of more than 3 oral aphthous ulcers or recurrent orogenital aphthae but do not satisfy the criteria for Behçet disease. We report a severe case of pediatric-onset complex aphthosis with poor response and/or significant toxicity to first-line medications. Lenalidomide, a second-generation immunomodulatory drug, induced a complete disease remission within few days of therapy. The patient has been treated for nearly 3 years with significant subjective and clinical improvement and no adverse effects. Thereby, lenalidomide may represent a well-tolerated and effective medication for patients with complex aphthosis who are intolerant or not responsive to first-line agents. Nevertheless, in view of the rare but serious potential adverse effects of lenalidomide such as teratogenicity and cancer, a clinical trial is necessary to assess the true risk-to-benefit ratio for the use of lenalidomide in patients with complex aphthosis.