A 31-year-old woman diagnosed with Lyme disease was treated with amoxicillin. One hour after the first antibiotic dose, the patient became acutely ill. She developed hypertension, fever, and rigors. Shortly afterward, she became hypotensive and required fluid resuscitation. This systemic illness, the Jarisch-Herxheimer reaction, was first noted in association with antibiotic therapy for neurosyphilis. Thus, the institution of antibiotic therapy may be complicated by the Jarisch-Herxheimer reaction.