Ubiquitin-conjugating enzyme E2S (UBE2S), a family of E2 protein in the ubiquitination process, is involved in the development of various cancers. However, its role in lung adenocarcinoma has not yet been well elucidated. In this report, we attempted to investigate the expression and function of UBE2S in lung adenocarcinoma. Up-regulation of UBE2S at mRNA and protein level was observed in human cancer tissues and lung adenocarcinoma cells. Higher UBE2S expression was correlated with poorer prognosis of lung adenocarcinoma patients. UBE2S expression was efficiently suppressed by lentivirus-mediated shRNA strategy in A549 cells and UBE2S silencing led to reduced cell proliferation, colony formation and enhanced apoptosis. Microarray analysis indicated that a large amount of genes were regulated by UBE2S and p53 signaling pathway might be critical to the role of UBE2S in cancer development. Taken together, UBE2S could be a potential target for lung adenocarcinoma.