Activation of hypothalamic orexin neurons is a potential mediator of the weight gain associated with some antipsychotic drugs. Male rats display increased Fos expression in lateral hypothalamic orexin neurons following clozapine administration; however, amphetamines led to increased Fos expression in medially located orexin neurons. The rhesus monkey (Macaca mulatta) provides a model to examine the relationships between orexin neurons, weight and physical activity. Using stereology, the number of orexin-A immunoreactive neurons was quantified in 18 male (7.6-18.3kg) and 18 female (4.8-12.2kg) monkeys. In females, there was no relationship between weight and medial or lateral orexin-A neuron number. Conversely, in male monkeys, higher body weight was significantly associated with less medial orexin-A neurons (P<0.05), but the relationship with lateral orexin-A neurons only approached significance (P=0.075). Of the 36 animals in which orexin-A neurons was estimated, activity was monitored for 21 days via an Actiwatch-64 in 12 males and 12 females. Weight was negatively associated with activity in males (P<0.05), but not females. Comparisons of activity to orexin-A neurons revealed a significant association between higher activity levels and greater numbers of orexin-A neurons in the medial hypothalamus (P<0.05) but not with those in the lateral hypothalamus of males. Females showed no relationship between orexin-A neurons in either region and activity. The significant relationship between weight, activity, and medial orexin-A neurons of males, indicates that in monkeys, the medially located orexin neurons may be more influential in mediating body weight than in the rodent. (Supported by NIH Grant-P01-AG00001-29 and RR-00165).