Recent studies have shown that thyrotropin-releasing hormone is present in gastrointestinal tissues and has effects on gastrointestinal motility and secretion. In the present study, we have investigated in healthy subjects the effects of various doses of thyrotropin-releasing hormone on secretin-cholecystokinin-stimulated pancreatic secretion. Intravenous infusion of thyrotropin-releasing hormone at doses of 4, 20, and 100 microgram/30 min, administered during a constant pancreatic stimulation with secretin (0.5 Clinical Units/kg/h) and cholecystokinin (0.5 Ivy dog units/kg/h), produced a significant decrease in lipase and chymotrypsin secretion without affecting volume and bicarbonate secretion. The decrease appeared immediately with the lowest dose of TRH employed, and was progressively more marked with increasing doses of the hormone. Compared with the control experiments, the maximal inhibition of lipase output reached -17.6%, -37.2%, and -43%, and the maximal inhibition of chymotrypsin output -18.2%, -39.3%, and -44.9%, for the three doses of thyrotropin-releasing hormone employed, respectively. It is concluded that TRH has a marked inhibitory effect on the enzymatic component of the pancreatic secretion stimulated by submaximal doses of secretin and cholecystokinin. The physiologic importance of this effect remains to be defined.