The products of somatostatin in the circulation have been investigated by high-pressure liquid chromatography. Plasma collected 1 min after intravenous injection of cyclic (oxidized) somatostatin showed a single ultraviolet absorbing peak. The total plasma content of this product was equivalent to 10--20% of the injected dose. Amino acid analysis showed that 80--90% of the material in the peak was [des-Ala1]-somatostatin and the remainder was unchanged peptide. [des-Ala1]-Somatostatin is rapidly formed in blood and plasma in vitro and according to other workers may be fully active. In contrast, 1 min after injection of linear (reduced) somatostatin, no products could be detected in the circulation. Incubations in vitro resulted in rapid conversion of the linear somatostatin to a product similar to the cyclic form. However, in vivo, very efficient clearance of linear somatostatin must occur even more rapidly than cyclization. In view of the very different clearance rates of the two forms of somatostatin, it is important to know whether endogenous somatostatin is released in the cyclic or the linear form. The absence of detectable concentrations of inactive peptide fragments in the circulation suggests that inactivation of somatostatin occurs in the tissues.