To examine clinical, etiologic, and histologic features of Stevens-Johnson syndrome and to identify possible correlates of clinical disease severity related to etiologic and histopathologic findings. This is a retrospective review of patients seen at Mayo Clinic between January 1, 2000, and December 31, 2007. Of 27 patients (mean age, 28.1 years), 22 (81%) had involvement of 2 or more mucous membranes, and 19 (70%) had ocular involvement. Medications, most commonly antibiotics and anticonvulsants, were causative in 20 patients. Mycoplasma pneumoniae infection caused 6 of the 27 cases. Corticosteroids were the most common systemic therapy. No patients with mycoplasma-induced Stevens-Johnson syndrome had internal organ involvement or required treatment in the intensive care unit, in contrast to 4 patients each in the drug-induced group. Three patients had chronic ocular sequelae, and 1 died of complications. Biopsy specimens from 13 patients (48%) showed epidermal necrosis (8 patients), basal vacuolar change (10 patients), and subepidermal bullae (10 patients). Biopsy specimens from 11 patients displayed moderate or dense dermal infiltrate. Histologic features in drug-induced cases included individual necrotic keratinocytes, dense dermal infiltrate, red blood cell extravasation, pigment incontinence, parakeratosis, and substantial eosinophils or neutrophils. Our clinical and etiologic findings corroborate those in previous reports. M pneumoniae-induced Stevens-Johnson syndrome manifested less severely than its drug-induced counterpart. The limited number of biopsies precludes unequivocal demonstration of histopathologic differences between drug-induced and M pneumoniae-induced Stevens-Johnson syndrome.