Somatostatin (SRIF) is effective in the nonoperative management of a variety endocrine tumors. A potential role of SRIF for treatment of patients with primary hyperparathyroidism (pHPT) has been suggested. In a controlled, prospective, triple-blinded, randomized clinical trial, the somatostatin analogue octreotide (SMS 201-995, Sandostatin) was evaluated in 40 patients with well documented pHPT. Amongst other biochemical parameters, serum calcium and-phosphate and levels of parathyroid hormone, calcitonin, and osteocalcin as well as octreotide were assessed before and for 4 hours after a single iv. application of 200 micrograms ocreotide or placebo. SRIF-receptor autoradiography was performed in parathyroid tissue samples. Baseline values revealed a constellation of biochemical parameters typically found in pHPT. Following 200 micrograms octreotide, no significant changes in any of the biochemical parameters investigated for were observed. Multivariate analysis was performed to identify patient subpopulations in which any given combination of laboratory parameters changed in response to either drug or placebo. However, no 'responders' to octreotide were identified. 45% of patients receiving octreotide, reported side effects. Parathyroid tissue samples were negative for SRIF-receptor expression. It is concluded that a single dose iv. application of octreotide does not result in appreciable changes of biochemical parameters relevant in pHPT and carries a high rate of side effects. Furthermore, absence of SRIF-receptors in parathyroid tissue from patients with pHPT, together with lack of octreotide effects, suggests that somatostatin-analogues may not be effective in the non-operative therapy of pHPT.