To determine whether recurrent episodes of appropriately treated Lyme disease are caused by reinfection or relapse, we monitored pertinent clinical manifestations and serology of residents of an endemic site each year for 14 years. Of 253 episodes of early Lyme disease recorded among 213 residents, we observed 40 recurrent episodes. Virtually all included an erythema migrans (EM) rash that appeared at body sites that differed from those of the initial rash, no subjects produced detectable levels of specific antibody between sequential episodes, all episodes occurred a year or more after the initial EM episode, and all occurred during late spring and early summer. People experiencing recurrent episodes tended to have frequent contact with vector ticks. Prompt administration of standard antibiotic therapy for early Lyme disease reliably eliminates persistent infection and prevents relapse.