We report two cases of Lyme disease in North Carolina, further expanding the distribution of known sporadic cases of this predominantly northeastern problem in southern states. Physicians in areas where Lyme disease has traditionally not been recognized should be alerted to its characteristic rash (erythema chronicum migrans), tick vector (Ixodes species), possible severe manifestations (neurologic, arthritic, and cardiac), and response to appropriate antibiotic therapy (penicillin or tetracycline).