The increased encroachment of humans into natural areas is typically viewed as stressful for many wildlife species. A common stress response of many animals, including snakes, is the elevated release of the adrenal hormone, corticosterone. To test whether human encounters elicited a stress response in snakes, we monitored the levels of circulating corticosterone in free-ranging Cottonmouths (Agkistrodon piscivorus) during staged interactions. When exposed to a high-level disturbance (i.e., capture and confinement in a bag) for 30 min, Cottonmouths exhibited a significant corticosterone stress response as predicted. This response was four times that of the control treatment (i.e., immediately bled snakes) and shows that Cottonmouths exhibit strong corticosterone responses to confinement. Conversely, blood corticosterone values for low-level disturbance (i.e., nearby human presence for 30 min) did not differ significantly from the control treatment. The lack of a strong stress response to low-level disturbance indicates that Cottonmouths possess a seemingly adaptive mechanism of not being overly alarmed by the mere presence of a potential predator. This suggests that the occasional foot-path encounters humans commonly have with snakes may not be stressful for some snake species.