The most common cutaneous side effects to epidermal growth factor receptor (EGFR) inhibitors are follicular or acneiform eruptions, nail disorders, xerosis, and desquamation. Although topical and oral antibiotics with or without topical corticosteroids usually are safe and effective treatment options for acneiform eruptions due to EGFR inhibitors, they are not always successful in refractory cases. We report 3 cases of severe acneiform eruptions induced by EGFR inhibitors that were successfully treated with oral isotretinoin. Complete response was observed in all 3 patients. We recommend oral isotretinoin for the management of acneiform reactions to EGFR inhibitors when the lesions persist or worsen despite antibiotic treatment.