Background Secondary syphilis, which typically begins 4-10 weeks after initial exposure to Treponema pallidum, manifests with a range of cutaneous patterns. One unusual variation features oval, targetoid plaques that may resemble erythema multiforme (EM). Methods We describe a 23-year-old woman with an EM-like eruption, a mucous patch, and a prominent alopecia somewhat moth-eaten in appearance. She had positive rapid plasma reagin and fluorescent treponemal antibody absorption (FTA-ABS) tests, and a skin biopsy revealed swollen endothelial cells with a superficial perivascular infiltrate containing plasma cells. Response to intramuscular penicillin therapy was consistent with the empiric diagnosis of secondary syphilis. Conclusions One should consider secondary syphilis in the differential diagnosis of an eruption resembling EM.