Purpose Some studies have indicated that using 500 mg/m2 rituximab combined with CHOP‐14 may be beneficial for elderly men but not women with diffuse large B‐cell lymphoma (DLBCL). The purpose of this study was to investigate the potential benefit of escalated doses of rituximab with CHOP‐21 as the first‐line treatment in male patients with DLBCL. Methods We performed a retrospective cohort study to analyze the survival benefit of rituximab 500 mg/m2 plus the CHOP‐21 regimen (Escalated‐R‐CHOP‐21) as the first‐line treatment compared with using rituximab 375 mg/m2 plus the CHOP‐21 regimen (Standard‐R‐CHOP‐21) in men with DLBCL. We used propensity score matching to maximize the balance of the observed covariables. The primary endpoints of this study were the progression‐free survival (PFS) rate and overall survival (OS) rate at 3 years. Results After a median follow‐up of 47 months (IQR 31–65), no significant difference in PFS and OS was found for men treated with Escalated‐R‐CHOP‐21 compared with Standard‐R‐CHOP‐21 3‐year PFS: 69.7% versus 71.9%, p = 0.867; 3‐year OS: 83.0% versus 82.4%, p = 0.660. After 1:1 propensity score matching, we found that the patients using Escalated‐R‐CHOP‐21 had statistically significant survival benefits relative to Standard‐R‐CHOP‐21 among the 96 matched elderly male patients for 3‐year PFS 75.5% (95% CI 62.8–88.2) versus 58.2% (95% CI 44.3–72.1); p = 0.019 and 3‐year OS 86.6% (95% CI 76.4–96.8) versus 65.8% (95% CI 52.1–79.5); p = 0.017. However, no differences in survival were observed for younger male patients. Furthermore, the dose effect in PFS of Escalated‐R‐CHOP‐21 was more obvious for elderly male patients with no high‐risk extranodal sites (p = 0.005 and interaction p = 0.030). Conclusion Escalated‐R‐CHOP‐21 could be a safe and effective option for treating elderly male patients with DLBCL. This study provides new insight into optimizing the standard treatment regimen, which may have important therapeutic implications in elderly male patients with DLBCL. In this study, we investigated the potential benefit of rituximab 500 mg/m2 plus the CHOP‐21 regimen (Escalated‐R‐CHOP‐21) as the first‐line treatment compared with using rituximab 375 mg/m2 plus the CHOP‐21 regimen (Standard‐R‐CHOP‐21) in male patients with DLBCL. We found that only elderly men had statistically significant survival benefits from Escalated‐R‐CHOP‐21 than Standard‐R‐CHOP‐21 of 3‐year PFS 75.5% (95% CI 62.8–88.2) vs. 58.2% (95%CI 44.3–72.1); p = 0.019 and 3‐year OS 86.6% (95% CI 76.4–96.8) vs. 65.8.0% (95% CI 52.1–79.5); p = 0.017 without causing severe toxicity after propensity score matching.