Somatostatin receptor gene expression of SSTR1, SSTR2, and SSTR3 subtypes was evaluated by in situ hybridization in 55 human primary tumors shown to contain a high density of somatostatin receptors in binding assays. All 55 tumors expressed at least one SSTR subtype. Of 55 somatostatin receptor-positive tumors, 46 had SSTR2 mRNA; all 46 were characterized as having receptors with a high affinity for the synthetic analogue octreotide. Of 55 tumors, 12 expressed SSTR1, and 14 expressed SSTR3 mRNA. The subtype SSTR1 was expressed alone in 4 cases, SSTR2 was expressed alone in 33 cases, and SSTR3 was expressed alone in one case. In 4 cases, all 3 SSTR were expressed simultaneously. The cases having SSTR1 mRNA were identified in binding experiments with 125I-labeled somatostatin-14 and -28 analogues rather than with 125I-[Tyr3]-octreotide. Whereas meningiomas, neuroblastomas, pituitary adenomas, small cell lung carcinomas, lymphomas, and breast tumors expressed primarily a high abundance of SSTR2, carcinoids, islet cell carcinomas, medullary thyroid carcinomas, and ovarian tumors had a mixed distribution of the somatostatin receptor subtypes. This is the first demonstration of the presence of SSTR1, SSTR2, and SSTR3 in primary human tumors using in situ hybridization. Since these somatostatin receptor subtypes probably mediate distinct somatostatin actions, it may be worthwhile to search for subtype-specific analogues to use for the treatment and diagnosis of these tumors.