The purpose of this study was to determine whether the increased expression of tyrosine hydroxylase (TH), the first and limiting enzyme in catecholamine synthesis in vasopressin (VP) neurons of the human neonate, represents a primary developmental phenomenon or reflects a secondary phenomenon related to the activation of VP systems due to perinatal hypoxia. Using immunohistochemistry, we investigated TH expression in the supraoptic nucleus (SON) of 15 human neonates at autopsy in relation to the age and severity/duration of hypoxic injury that was estimated on the basis of neuropathological criteria. Increased expression of TH was observed selectively in VP-synthesizing neurons of neonates who experienced prolonged perinatal hypoxia; was not related to the age, body weight/percentile, brain weight, or head perimeter of the subjects but depended on the neuropathological grade of the hypoxic injury (p < 0.01); and was found in VP-synthesizing neurons with increased cellular and nuclear size, that is, neurons with histological evidence of activation. Taken together, these observations indicate that increased expression of TH in VP neurons of SON is not developmentally determined but represents a response to hypoxic stress. We propose that increased TH expression in SON neurons of the human neonate may serve as a neuropathological marker of prolonged perinatal hypoxia in autopsy material.