Protein ubiquitination has been reported to be involved in many biological processes that affect cancer cell growth or death. In this study, we identified differentially expressed E3s/DUB-related genes associated with the prognosis of lung adenocarcinoma and then constructed an E3s/DUB enzyme signature prediction model for the training group and validated its accuracy for prognosis prediction in the validation group. According to our constructed model, all patients were divided into the high- or low-risk group, and a comparison of the two groups revealed that the high-risk group had poorer survival and higher mortality than the low-risk group. The calculated risk score was also an independent prognostic factor when analyzed together with other clinical factors. To explore the functions of the signature genes, we predicted the substrate proteins with which they interact and then performed enrichment analysis. Interestingly, we found that the signature genes were enriched in multiple treatment resistance and immune-related pathways. Therefore, we continued to analyze immune infiltration in the samples and found a variety of differences in immune cell infiltration. According to our constructed model, these differences in immune cell infiltration may predict different immune statuses after grouping and are associated with worse prognosis in high-risk patients.