Sub chronic exposure to lead in rats slows gastric emptying, but little is known about the effects of lead on gastric secretion. This study was designed to investigate the effects of lead on gastric acid secretion and its possible mechanisms in rats. Lead acetate was dissolved in drinking water in a concentration of 1%. Sodium acetate-containing water with a molar concentration similar to lead was also prepared. We had nine groups of animals (n=8); four of them were exposed to lead for 1, 2, 3, and 4 weeks (Pb1, Pb2, Pb3 and Pb4 groups, respectively). Sodium acetate solution was given to another four groups for 1, 2, 3, and 4 weeks (Na1, Na2, Na3 and Na4 groups, respectively). Gastric secretion was collected by washout technique and its acid output was measured in the basal (Basal Acid Output, BAO), vogotomy (Vagotomized Acid Output, VAO), and vagally stimulated (Vagally Stimulated Acid Output, VSAO) states using titrator instrument. Nitric oxide (NO) metabolite of gastric tissue was determined by Griess micro assay method to evaluate the possible mechanism of lead effect on gastric secretion. VSAO was significantly less in Pb1 and Pb2 groups than Na1 and Na2 ones respectively (1.75 ± 0.17, 2.10 ± 0.30 vs. 5.79 ± 0.20, 6.18 ± 0.27 µmol/15min) (P=0.001, P=0.001). BAO was significantly more in Pb3 and Pb4 groups than Na3 and Na4 ones respectively (2.77 ± 0.37, 2.80 ± 0.31 vs. 1.73 ± 0.16, 1.79 ± 0.34 µmol/15min) (P=0.01, P=0.02), but it was the same after vagotomy. VSAO was more in Pb3 and Pb4 groups than their Na counterparts (P=0.001, P=0.0001). NO metabolite of gastric tissue was more in all Pb groups in comparison to their Na counterparts (P=0.0001). In this study, it seems that lead exposure, via NO mechanism, has different effects on acid secretion. Nitric oxide in small and large amounts decrease and increase gastric acid secretion, respectively.