The effect of rostral deafferentation of the medial basal hypothalamus (MBH) on delta-9-tetrahydrocannabinol (THC)-induced changes in serum prolactin (PRL) concentrations was investigated in female rats having retrochias-matic frontal cuts that transected the rostral hypothalamus. Cuts dorsal to the hypothalamus were produced in the same plane in other animals in order to control for possible effects of the surgical procedure or dorsal brain damage. All animals were ovariectomized 28–35 days after stereotaxic surgery to obviate potential confounding effects of differences in ovarian function between groups. Unlesioned rats were ovariectomized to provide a positive control group for THC inhibitory activity. At least 4 weeks after ovariectomy, animals were treated intravenously with THC (0.5 or 1.0 mg/kg body weight) or vehicle at the midpoint of a 110-min experimental period during which blood samples were obtained at 10-min intervals via indwelling atrial cannulae. Serum PRL concentrations were determined by radioimmunoassay and cut locations were confirmed histologically. When administered to ovariectomized animals without brain lesions, THC suppressed serum PRL concentrations from the average treatment level within 30 min (p < 0.05), and PRL levels remained suppressed for the remainder of the posttreatment sampling period. Treatment with the vehicle alone was without effect. Animals with retrochiasmatic plane cuts that did not transect the rostral hypothalamus similarly displayed PRL suppression in response to THC administration (p < 0.05). In contrast, THC administration to animals having retrochiasmatic cuts complete to the base of the brain produced a prompt PRL rise which peaked 10 min after treatment (p < 0.05) and then declined to, but not significantly below, the average pretreatment PRL level. The PRL rise (5-fold) following treatment with 1 mg THC/kg body weight was greater than that which followed treatment with 0.5 mg/kg body weight (p < 0.01). Serum PRL was not increased by treatment with the vehicle alone. These results indicate that transections of the rostral hypothalamus which separated the suprachiasmatic region from the MBH resulted in an apparent reversal of the acute effect of THC on serum PRL concentrations in that the sustained PRL inhibition that typically followed THC administration to unlesioned rats was converted to an abrupt, albeit brief PRL rise without evidence of subsequent suppression below pretreatment levels. While the mechanism of the THC-induced PRL rise remains unknown, the absence of PRL suppression in animals with rostral deafferentation of the MBH suggests that THC does not inhibit PRL secretion by directly promoting the release of PRL-inhibiting factor from median eminence nerve terminal