The long-term effect of hypothalamic lesions onplasma and pituitary levels of melanocyte-stimulating hormone (MSH) was examined in male rats. Lesions of the paraventricular nuclei (PVN) produced a large increase in both plasma and pituitary MSH levels, whereas lesions of the supra-optic nuclei had little effect. These results support the idea that MSH secretion is under an inhibitory control by the hypothalamus and suggest that the PVN are involved. The PVN may be involved in the release or production of an MSH release inhibiting factor (MIF), although the present results do not exclude the possibility that the PVN control MSH secretion through a direct innervation of the pars intermedia.