Environmental stimulation results in an increased expression of transcription factors called immediate early genes (IEGs) in specific neuronal populations. In male Japanese quail, copulation with a female increases the expression of the IEGs zenk and c-fos in the medial pre-optic nucleus (POM), a key nucleus controlling male sexual behavior. The functional significance of this increased IEG expression that follows performance of copulatory behavior is unknown. We addressed this question by repeatedly quantifying the performance of appetitive (learned social proximity response) and consummatory (actual copulation) sexual behavior in castrated, testosterone-treated males that received daily intra-cerebroventricular injection of an antisense oligodeoxynucleotide targeting c-fos or control vehicle. Daily antisense injections significantly inhibited the expression of copulatory behavior as well as the acquisition of the learned social proximity response. A strong reduction of the proximity response was still observed in antisense-treated birds that copulated with a female, ruling out the indirect effect of the absence of interactions with females on the learning process. After a 2-day interruption of behavioral testing but not of antisense injections, birds were submitted to a final copulatory test that confirmed the behavioral inhibition in antisense-injected birds. Brains were collected at 90 min after the behavioral testing for quantification of c-fos-immunoreactive cells. A significant reduction of the number of c-fos-positive cells in the POM but not in other brain regions was observed following antisense injection. Taken together, the data suggest that c-fos expression in the POM modulates copulatory behavior and sexual learning in male quail.