BACKGROUND: TRIM proteins are important members of E3 ubiquitin ligases, and many studies have confirmed that TRIM family members play an important role in the development of various tumors. We found that TRIM59 expression level in non-small cell lung cancer (NSCLC) was significantly increased through second-generation sequencing. The purpose of this study was to investigate the expression of TRIM59 in NSCLC and its relationship with the clinicopathological parameters as well as the prognosis of patients. METHODS: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were excavated to analyze the expression of TRIM59 mRNA in NSCLC and its relationship with the prognosis of patients; The expression of TRIM59 protein in 90 tumor tissues and adjacent tissues was detected by immunohistochemical staining, and the relationship between the expression of TRIM59 protein and clinicopathological parameters and prognosis was analyzed. RESULTS: Overexpression of TRIM59 mRNA in tumor tissues predicted poor prognosis. The expression level of TRIM59 protein was significantly higher in tumor tissues than in adjacent tissues, and TRIM59 protein expression was correlated with tumor size (P=0.007), tumor differentiation (P=0.009), tumor-node-metastasis (TNM) stage (P=0.003) and lymph node metastasis (P=0.003). Multivariate Cox regression analyses showed that along with TNM stage, overexpression of TRIM59 could be considered an independent prognostic factor for NSCLC patients. CONCLUSIONS The expression of TRIM59 is closely related to the prognosis of NSCLC patients, and it is an independent risk factor for NSCLC patients.