Technical Abstract: Gastric acid secretion is a complex process regulated by neuronal and hormonal pathways. Ex vivo studies in human gastric tissues indicate that the calcium sensing receptor (CaR), expressed on the surface of G and parietal cells, may be involved in this regulation. We sought to determine whether cinacalcet, a CaR allosteric agonist, increases serum gastrin levels and gastric acid secretion. The study we conducted was an 18-day randomized placebo-controlled double-blind trial with a fixed metabolic diet in a metabolic research unit at an academic medical center. Seventeen healthy subjects age 45-70 with normal gastric acid output participated in the study. Exclusion criteria included diseases and medications known to affect gastric acid and calcium balance. On day 8 (baseline), subjects were given cinacalcet (15 then 30 mg daily) or placebo for 11 days. Basal and maximal gastric acid output and serum gastrin level were the main outcome measures. Study results showed that baseline basal and maximal gastric acid output and serum gastrin levels were similar between groups. However, changes in serum gastrin and basal acid output (adjusted for baseline weight) were significantly more positive in the cinacalcet group compared to placebo (P=0.004 and P=0.039, respectively). Change in maximal acid output was similar in the 2 groups (P=0.995). As expected, cinacalcet produced significant decreases in serum PTH (P<0.001) and ionized calcium levels (P=0.032), and increases in serum phosphorus levels (P=0.001) and urinary calcium excretion (P=0.023). This study provides in vivo evidence that activation of the CaR increases serum gastrin levels and basal gastric acid secretion in healthy adults.