Gastric cancer (GC), as one of the most prevalent malignancies, contributes to the high morbidity and mortality worldwide. By analyzing the bioinformatics, qRT-PCR and IHC assays, we found that CLEC5A is overexpressed in GC and associated with poorer prognosis. CLEC5A silencing inhibits cell growth and DNA replication and induces cell cycle arrest and cell apoptosis. Bioinformatics analyses and Western blotting revealed that CLEC5A depletion led to the dysregulation of the PI3K/AKT/mTOR pathway. CLEC5A-mediated GC proliferation and anti-apoptosis were impaired by blocking the PI3K/AKT/mTOR pathway with LY294002. We hypothesize that CLEC5A is of vital importance to GC initiation and progression via the PI3K/AKT/mTOR pathway, and that our results might represent promising therapeutic strategies for GC patients. (C) 2019 Published by Elsevier Inc.