BACKGROUNDChronic atrophic gastritis (CAG) is an important precursor of gastric cancer(GC), and there is currently a lack of reliable non-invasive diagnostic markers. This study aims to find a biomarker for non-invasive screening of CAG in the community.METHODSA total of 540 individuals were enrolled (test set = 385, validation set = 155). ROC curve analysis was used to evaluate the diagnostic significance of serum Trefoil Factor 3 (TFF3) alone or in combination with pepsinogen (PG) for CAG in the test and validation set. Furthermore, the diagnostic value of TFF3 and PG in different Helicobacter pylori (H. pylori) infection states was studied.RESULTSWhen compared with chronic superficial gastritis (CSG), the expression level of serum TFF3 in the CAG was higher (27 ng/ml vs 19.61, P < 0.001). ROC curve analysis found that the sensitivity, specificity, and area under the curve (AUC) of CAG diagnosis using serum TFF3 alone at the optimal cut-off value of 26.55 ng/ml were 0.529, 0.87, and 0.739, respectively. When TFF3 was combined with The Ratio of PGI to PGII (PGR), the AUC and specificity reached 0.755 and 0.825, respectively. TFF3 individual or combined with PGR had good predictive value, especially in the H. Pylori negative patients.CONCLUSIONTFF3 combined with PGR can effectively predict CAG, especially in patients with H. pylori negative.