Purpose: Histone lysine methyltransferase 2D (KMT2D/MLL2) is a known cancer-related protein; however, its function in gastric cancer (GC) remains uncharacterized. The present study sought to investigate the expression pattern and the role of KMT2D in GC. Methods: The expression of KMT2D were evaluated at mRNA and protein levels, while its clinicopathological value were further explored. GC cells were transfected with KMT2D knockdown siRNAs or lentiviruses, and then detected by cell counting kit-8, plate clone formation, cell apoptosis, cycle, migration, invasion, and tumorigenesis assays. Results: Overexpression of KMT2D was observed in GC samples, and was strongly associated with poor survival. Depletion of KMT2D suppressed cell proliferation and induced apoptosis. Conclusion: Our study demonstrated the upregulation of KMT2D in GC tissue, and KMT2D modulates proliferation and apoptosis in GC. Therefore, KMT2D might represent a novel oncogene for prognosis and optimal treatment of GC patients. (C) 2018 Elsevier Inc. All rights reserved.