OBJECTIVE To examine clinical associations, evolution of the condition, and response to treatment of erythema multiforme (EM) in prepubertal children. METHODS A retrospective case series evaluation of children younger than 13 years with EM. METHODS Ambulatory care university hospital. METHODS Referral patients from pediatricians serving a population of 3.2 million. METHODS Results of treatment of each EM episode with topical acyclovir or oral acyclovir at a dose of 25 mg/kg per day and 6-month prophylaxis with oral acyclovir at a dose of 20 mg/kg per day were evaluated. RESULTS Age at EM onset, preceding illness, and number and duration of episodes during a 3-year period were recorded. RESULTS Twelve children (7 boys and 5 girls) in whom herpes simplex virus (HSV)-associated EM developed were evaluated. Preceding lesions were herpes labialis in 8 children and herpes facialis in 2 children. Two children had no obvious HSV lesion. The mean age at onset of disease was 8.1 years, and the mean time from the preceding HSV to the onset of skin lesions was 3.9 days (range, 0-11 days). Episodes of EM lasted a mean of 10.6 days. In 9 children, the EM was recurrent, with a mean of 2.6 episodes per year. All 12 children, including those with negative viral cultures for HSV or no HSV history had HSV detected in their target lesions by polymerase chain reaction amplification of DNA obtained from skin biopsy specimens. Six of 12 children were treated with oral acyclovir at a dose of 25 mg/kg per day for 1 or more individual episodes, without reduction in the episode. Three children underwent 6-month prophylaxis with oral acyclovir at a dose of 20 mg/kg per day and remained disease free during treatment. After discontinuation of the prophylactic treatment with acyclovir, 1 child relapsed at 4 months. The other 2 children had no further episodes during a 3-year period. CONCLUSIONS The HSV-associated EM is a recurrent disease that can be precipitated by sun exposure and does not progress to Stevens-Johnson syndrome. Childhood HSV-associated EM may be unresponsive to treatment with oral steroids or oral or topical acyclovir. Frequent recurrences of EM may be abrogated by prophylactic treatment with acyclovir.