Lyme disease is a zoonosis found throughout France, with the exception of the Mediterranean coast and high-altitude areas. While its presence is well documented in the northeastern quarter of France, little is known about it in the southwestern quarter. From May 2010 to April 2012, two French regions, Aquitaine and Franche-Comté, conducted a descriptive and prospective epidemiological study through a Lyme borreliosis surveillance network, based on a sample of volunteer general practitioners and specialists—both private practitioners and hospital-based physicians—distributed throughout each region. The objectives of these studies were to describe the disease, estimate its incidence, and improve diagnostic, therapeutic, and preventive practices.