Recent studies have proposed that p38gamma (p38 gamma) might be critically involved in tumorigenesis and cancer progression. Its expression and potential functions in human renal cell carcinoma (RCC) are studied here. We show that p38 gamma mRNA and protein levels are upregulated in human RCC tissues, as compared to its levels in the surrounding normal renal tissues. p38 gamma upregulation was also detected in established (786-O line) and primary human RCC cells. Functional studies in 786-0 cells and primary human RCC cells demonstrated that p38 gamma silencing (by targeted shRNAs) or CRISPR/Cas9-mediated p38 gamma knockout (KO) potently inhibited cell growth, viability, proliferation and migration. Furthermore, p38 gamma shRNA or KO in RCC cells decreased retinoblastoma (Rb) phosphorylation and downregulated cyclin E1/A expression. Additionally, significant apoptosis activation was detected in p38 gamma-silenced and p38 gamma-KO RCC cells. Contrarily, ectopic overexpression of p38 gamma facilitated cell growth, viability, proliferation and migration in RCC cells. Taken together, we show that p38 gamma overexpression promotes RCC cell growth, proliferation and migration. p38 gamma could be a novel therapeutic target for human RCC. (C) 2019 Elsevier Inc. All rights reserved.