The plasma levels of glucocorticoid hormones (e.g., corticosterone and cortisol) are often used as an index of physiological stress. However, under natural conditions, glucocorticoid secretion can respond to both environmental influences (e.g., extreme climatic conditions) and internal influences (populational differences and annual seasonal cycles). To distinguish between these kinds of influences, we examined seasonal variation in basal levels of corticosterone and the adrenocortical response to acute stress in six populations of western fence lizards Sceloporus occidentalis. Three populations (Mojave CA, Lone Pine CA, and Tulalip WA) were near the periphery of the species distribution, and three were in the central part of the range (Ojai CA, Hopland CA, and Bend OR). Basal corticosterone showed no consistent pattern of variation, but the adrenocortical response to acute stress was consistently highest 1) in populations living at the margin of the species range, 2) during the hottest and driest seasons, and 3) in individuals with the largest decrements in physiological condition (length-adjusted mass). Thus, basal adrenal secretion and adrenal responsiveness to acute stress were dissociated, and the latter more likely reflected the physiological condition of an individual and the severity of its environment. However, further analysis showed that physiological condition only partially explains the variation in adrenocortical responsiveness and that intrinsic seasonal and population differences may be as important as the external influences of the physical environment. After factoring out seasonal changes in physiological condition, adrenocortical response of two populations under identical controlled laboratory conditions also showed that a peripheral population (Mojave, CA) maintained a higher response than a central population (Bend, OR) that was not attributable to population differences in physiological condition.