Although recent reports of global amphibian declines have received considerable attention, reptile declines have gone largely unreported. Among reptiles, snakes are particularly difficult to quantitatively sample, and thus, most reports of snake declines are based on qualitative or anecdotal evidence. Recently, several sources have suggested that Eastern Kingsnakes (Lampropeltis getula) have declined over a substantial portion of their range in the southeastern United States, particularly in Florida. However, published evidence for L. getula declines or their potential causes are limited. We monitored the status of a population of L. getula on the U.S. Department of Energy's Savannah River Site (SRS) in Aiken, South Carolina, USA, from 1975 to 2006. Herpetofaunal populations on the Savannah River Site have been protected from the pressures of collecting and development since 1951 due to site access restrictions. Here, we document a decline in both abundance and body condition of L. getula inhabiting the vicinity of a large isolated wetland over the past three decades. Because this L. getula population was protected from anthropogenic habitat degradation, collection, and road mortality, we are able to exclude these factors as possible causes of the documented decline. Although the definitive cause of the decline remains enigmatic, natural succession of the surrounding uplands, periodic extreme droughts, shifts in community composition (e.g., increased Agkistrodon piscivorus abundance), introduced fire ants, or disease are all potential contributors to the decline.