We have examined the utility of in situ hybridization for detecting pre-prosomatostatin mRNA in postmortem human brain. In preliminary studies, Northern blot analysis using a rat model, which simulates the normal pattern of human post-mortem brain cooling, revealed retention of significant amounts of hybridizable somatostatin mRNA relative to control levels between 12 and 24 hours after death. mRNA extracted from postmortem fetal human brain specimens showed hybridization to cRNA probes directed against pre-prosomatostatin mRNA. We thus undertook in situ hybridization studies. Antisense RNA probes were hybridized to neurons that expressed pre-prosomatostatin in 10-microns sections of adult and fetal human brain. The distribution of pre-prosomatostatin mRNA-containing neurons was similar to that observed for somatostatin-like immunoreactivity; however, the in situ hybridization technique was a more sensitive marker of neuronal perikarya. Our results indicate that hybridization to pre-prosomatostatin mRNA is a useful method for localizing these peptidergic neurons in postmortem human brain tissue.