A double-label immunofiuorescence technique was used to determine whether progesterone receptor (PR)-containing neurons in the preoptic area and hypothalamus also contain somatostatin (SOM) in both the male and female guinea pig. Animals were gonadectomized, primed by estradiol to induce PR and injected intracerebroventricularly with colchicine to visualize SOM-immunoreactive (SOM-IR) neurons. The only sites of significant overlap between the two immunoreactivities were the medial preoptic nucleus, the periventricular preoptic and hypothalamic regions, the arcuate nucleus (Ar) and the ventrolateral nucleus (VL). No sex differences were detected at this level. In the preoptic area and the periventricular regions, no SOM-IR neurons were shown to have PR. In the Ar, only very few SOM-IR perikarya were found to be also PR-IR. SOM varicosities appeared in close proximity to neurons with PR-containing nuclei. Within the VL, in the female as well as in the male, many SOM-IR cells were also IR for PR. This colocalization persisted throughout the rostrocaudal extent of the nucleus but our quantification revealed a significant sex difference in the percentage of PR-IR neurons with SOM in the caudal VL. These results provide neuroanatomical evidence that progesterone may exert its effect directly upon more than one third of SOM-synthesizing cells in the medial and caudal regions of VL, a site which plays a key role in the control of sexual behavior.