The peptide alpha-melanocyte-stimulating hormone (alpha-MSH) occurs within the pituitary, brain, skin, ovary and other tissues, and has potent anti-inflammatory activity. For this reason, we examined its effects on an autoimmune disease: the experimental autoimmune-oophoritis (EAO). We analyzed the effect of the peptide on the release of nitric oxide (NO) and progesterone from cultured ovarian granulosa (GL) cells at 0, 7, 14, 21 and 28 days after sensitization of the rats. On day 0 the progesterone levels were higher in estrous rats than those in proestrus and diestrus. The NO amount did not differ among the diverse days of the cycles. The administration of alpha-MSH induced a decrease of NO in estrus and diestrus, but did not affect progesterone release. The EAO rats showed a period of constant diestrus ranging from about 7 to 14 days after immunization. At the onset (day 7) and the end of this period (day 14), the NO significantly increased in estrous rats which was correlated with a reduction in progesterone concentration. This effect was reverted by alpha-MSH. At 21 and 28 days, progesterone release increased only when the rats were in proestrus, while NO production was similar to that on day 0. Administration of alpha-MSH reduced progesterone release when the rats were in proestrus and these results were correlated with an increase in NO only at day 14. The results obtained suggest that alpha-MSH could act as a modulator of EAO, specially when the rats are in estrus.