Lyme disease is the most common tick-borne infection in the United States and Europe. A surprising number of patients experience a subsequent episode of Lyme disease after the first episode has resolved. Reinfection has been well-documented only after successfully treated early infection (nearly always erythema migrans) and can often be recognized clinically by the development of a repeat episode of erythema migrans occurring at a different location on the skin during months when the principal tick vectors are abundant in the environment. Limited data suggest that the clinical and laboratory manifestations of reinfection in patients with Lyme disease with erythema migrans are not very different from those of initial infection. Patients with recurrent infections afford an opportunity to study the role of the immune response in this illness. Because patients with early Lyme disease continue to remain at high risk for reinfection, this population should be targeted for education about prevention of Lyme disease.