OBJECTIVE: Limited data about the prognostic significance of mutations and copy number variations in diffuse large B-cell lymphoma (DLBCL) are available. This study aimed to comprehensively describe genetic alterations in DLBCL patients, and examine correlation of , and other genetic alterations with outcomes in patients treated with R-CHOP. METHODS: Probe capture-based high-resolution sequencing was performed on 191 patients diagnosed with DLBCL. MYC, BCL2, and BCL6 protein expressions were detected by immunohistochemistry. RESULTS: The presence of alterations significantly correlated with poor progression-free survival (PFS) (5-year PFS: 13.7% 40.8%; = 0.003) and overall survival (OS) (5-year OS: 34.0% 70.9%; = 0.036). Importantly, patients who harbored gain/amplifications () also had a remarkably inferior 5-year PFS (11.1% 38.3%; < 0.001) and OS (22.1% 69.6%; = 0.009). In contrast, neither mutations nor translocations were significantly prognostic for survival. Multivariable analyses showed that the presence of alterations, especially , mutations, and International Prognostic Index (IPI) were significantly associated with inferior PFS and OS. Novel prognostic models for OS were constructed based on 3 risk factors, including alterations (Model 1) or (Model 2), mutations, and IPI, to stratify patients into 4 risk groups with different survival outcomes. CONCLUSIONS: This study showed that DLBCL patients treated with R-CHOP, alterations, especially and mutations were significantly associated with inferior outcomes, which were independent of the IPI. The novel prognostic models we proposed predicted outcomes for DLBCL patients treated with R-CHOP, but further validation of the prognostic models is still warranted.