The role of capsaicin-sensitive afferent innervation and neural pathways involved in the enterogastric inhibition of gastric acid secretion by luminal acid was investigated in urethan-anesthetized rats. Intestinal perfusion with graded concentrations of HCl (50, 75, and 100 mM) for 1 h dose dependently inhibited both thyrotropin-releasing hormone (TRH) analogue- and pentagastrin-stimulated acid output (P < 0.01). The inhibitory effect of intestinal perfusion with HCl (100 mM) on pentagastrin-stimulated acid secretion was blocked by bilateral vagotomy, whereas celiac ganglionectomy had no effect. Systemic capsaicin pretreatment (125 mg/kg sc) reduced the antisecretory effects of luminal acid on both TRH analogue- and pentagastrin-stimulated acid secretion. Neither selective perivagal nor selective periceliac capsaicin treatments (1% solution) modified the antisecretory effect of intestinal perfusion with HCl (75 mM) on TRH analogue-stimulated acid secretion. However, combined selective perivagal plus periceliac capsaicin treatment reduced it to the same extent as systemic capsaicin treatment. We conclude that enterogastric inhibition of acid secretion by luminal acid in urethan-anesthetized rats is mediated by extrinsic reflexes involving both vagal and splanchnic capsaicin-sensitive afferent fibers.