Abstract Lung adenocarcinoma is the most prevalent lung cancer type. Ubiquitination, a critical post-translational modification process that regulates protein degradation and signaling pathways, has been implicated in various cancers, including LUAD. We aimed to explore the associations between ubiquitination and lung adenocarcinoma. TCGA-LUAD cohort served as the training set. Unsupervised clustering, univariate Cox regression, Random Survival Forests, and least absolute shrinkage and selection operator (LASSO) Cox regression were applied to identify ubiquitination-related genes (URGs), then ubiquitination-related risk scores (URRS) were calculated using gene expression and the univariate Cox’s coefficient. Comparisons between the high and the low URRS group regarding chemotherapy drug response, immune infiltration level, tumor mutation burden (TMB), tumor neoantigen load (TNB), PD1/L1 expression, and enriched pathways were performed. URRS was calculated based on the expression of DTL, UBE2S, CISH, and STC1. Patients with higher URRS had a worse prognosis (Hazard Ratio [HR] = 0.54, 95% Confidence Interval [CI]: 0.39–0.73, p