Background: Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease, and about 30%-40% of patients will develop relapsed/refractory DLBCL. In this study, we aimed to develop a gene signature to predict survival outcomes of DLBCL patients based on the autophagy-related genes (ARGs).Methods: We sequentially used the univariate, least absolute shrinkage and selector operation (LASSO), and multivariate Cox regression analyses to build a gene signature. The Kaplan-Meier curve and the area under the receiver operating characteristic curve (AUC) were performed to estimate the prognostic capability of the gene signature. GSEA analysis, ESTIMATE and ssGSEA algorithms, and one-class logistic regression were performed to analyze differences in pathways, immune response, and tumor stemness between the high- and low-risk groups.Results: Both in the training cohort and validation cohorts, high-risk patients had inferior overall survival compared with low-risk patients. The nomogram consisted of the autophagy-related gene signature, and clinical factors had better discrimination of survival outcomes, and it also had a favorable consistency between the predicted and actual survival. GSEA analysis found that patients in the high-risk group were associated with the activation of doxorubicin resistance, NF-kappa B, cell cycle, and DNA replication pathways. The results of ESTIMATE, ssGSEA, and mRNAsi showed that the high-risk group exhibited lower immune cell infiltration and immune activation responses and had higher similarity to cancer stem cells.Conclusion: We proposed a novel and reliable autophagy-related gene signature that was capable of predicting the survival and resistance of patients with DLBCL and could guide individualized treatment in future.