BACKGROUND: The clinical and genetic characteristics, as well as treatment outcomes, of diffuse large B-cell lymphoma (DLBCL) patients with different MYD88 and CD79B mutation status merit further investigation. OBJECTIVE: This study aims to investigate the distinctions in clinical manifestations, genetic characteristics, and treatment outcomes among MYD88-CD79B, MYD88/CD79B, and MYD88-CD79B DLBCL patients. PATIENTS AND METHODS: Clinical and genetic characteristics, along with treatment outcomes among 2696 DLBCL patients bearing MYD88-CD79B, MYD88/CD79B, and MYD88-CD79B treated with R-CHOP/R-CHOP-like regimens from the Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and six external cohorts were analyzed. Potential molecular mechanisms were investigated through Gene Set Enrichment Analysis and xCell methodology. RESULTS: In the MCD subtype, patients with MYD88-CD79B showed comparable progression-free survival (PFS) and overall survival (OS) compared to MYD88/CD79B or MYD88-CD79B. However, in the non-MCD subtype, patients with MYD88-CD79B exhibited significantly inferior OS than MYD88/CD79B or MYD88-CD79B, while there was no significant OS difference between MYD88/CD79B and MYD88-CD79B (median OS: 68.8 [95% CI 22-NA] vs NA [95% CI 112-NA] vs 177.7 [95% CI 159-NA] months; MYD88-CD79B vs MYD88/CD79B: p = 0.02; MYD88-CD79B vs MYD88-CD79B: p = 0.03; MYD88/CD79B vs MYD88-CD79B: p = 0.33). Regarding patients with MYD88-CD79B, there was no significant difference in PFS and OS between the MCD and non-MCD subtypes. Within the MYD88-CD79B group, patients with PIM1 had better PFS than PIM1 (median PFS: 8.34 [95% CI 5.56-NA] vs 43.8 [95% CI 26.4-NA] months; p = 0.02). Possible mechanisms contributing to the superior PFS of PIM1 patients may include activated lymphocyte-mediated immunity and interferon response, a higher proportion of natural killer T cells and plasmacytoid dendritic cells, as well as suppressed angiogenesis and epithelial-mesenchymal transition, along with lower fibroblast and stromal score. CONCLUSIONS: In the MCD subtype, patients with MYD88-CD79B showed comparable PFS and OS compared to MYD88/CD79B or MYD88-CD79B, while in the non-MCD subtype, they exhibited significantly inferior OS. There was no significant disparity in PFS and OS of MYD88-CD79B between the MCD and non-MCD subtypes. The presence of PIM1 within the MYD88-CD79B group correlated with better PFS, which may result from an intricate interplay of immune processes and tumor microenvironment alterations.