Early disseminated Lyme disease can be difficult to diagnose because of atypical symptoms and physical findings. A clinical diagnosis must be made in the absence of confirmatory serologic testing to allow timely therapy. We report a case of a 69-year-old woman who presents with fever, Horner syndrome, and a 12-cm oval-shaped erythematous macular rash with multiple vesiculopustular eruptions. The patient recovered after appropriate intravenous antibiotics, but serologic testing only confirmed the diagnosis 4 weeks later. This case also describes an unusual complication involving the neurologic system. We illustrate the clinical presentation and review the medical literature. Lyme disease should always be considered in patients from endemic regions with viral-like symptoms or a new rash.