Thirty patients hospitalized for induction chemotherapy of acute leukemia were studied for incidence, severity, and clinical features of oral herpes simplex virus infections. In 50% of the patients with evidence of past herpes infection, recurrent oral herpes developed during the study. Herpes simplex virus was the major cause of oral mucosal lesions seen in patients with leukemia. A majority of the episodes involved multiple oral sites and caused large atypical lesions. All lesions healed after topical or intravenous acyclovir therapy. Herpes simplex infection should be ruled out in all cases of oral ulcers detected in patients being treated for leukemia.