Background and Aims Primary hepatic diffuse large B-cell lymphoma (DLBCL) is rare and carries a poor prognosis, with no large-scale evidence supporting the value of chemotherapy. This study used real-world, large-sample data from the SEER database to evaluate the prognostic impact of chemotherapy in patients with primary hepatic DLBCL.Methods Clinical data of patients pathologically diagnosed with primary hepatic DLBCL between 2000 and 2019 were extracted from the SEER database and grouped according to whether they received chemotherapy. Kaplan–Meier survival analysis, Cox proportional hazards models, and random survival forest models were employed to identify factors influencing overall survival (OS) and cancer-specific survival (CSS), and subgroup analyses were performed.Results A total of 594 patients were included, with a median age of 66 years; 435 (73.2%) received chemotherapy. After a median follow-up of 17.5 months, the median OS was 81 (7-173) months in the chemotherapy group versus 11 (2-171) months in the non-chemotherapy group. The OS and CSS rates in the chemotherapy group were significantly higher than those in the non-chemotherapy group (67.99% vs. 47.77%; 71.03% vs. 52.87%, both P<0.05). Multivariate analysis showed that chemotherapy was an independent protective factor for OS (HR=0.39, 95% CI=0.31-0.48) and CSS (HR=0.37, 95% CI=0.29-0.48). In the random survival forest model, chemotherapy ranked highest in variable importance. Subgroup analyses produced consistent results.Conclusion Chemotherapy is an independent prognostic factor for patients with primary hepatic DLBCL and can significantly improve survival. The R-CHOP regimen may be the preferred therapeutic option.