Purpose <p>Central nervous system (CNS) relapse is associated with poor survival, and remains an unmet challenge in patients with diffuse large B-cell lymphoma (DLBCL). Identifying patients at high risk of CNS relapse and offering prophylactic treatment could improve patient prognosis.</p> Methods <p>Here, we studied 234 patients with DLBCL using open patient-level clinical and sequencing data to explore risk factors for CNS relapse. Patients were divided into Cohort A (CNS involvement at baseline), Cohort B (CNS recurrence), and Cohort C (patients without secondary CNS involvement and with a follow-up interval &gt; 3&#xa0;years). We investigated the risk factors for CNS relapse in Cohorts B + C.</p> Results <p>Genetic alterations with statistical significance, determined by univariate analysis, and an incidence rate ≥ 5%, together with clinical factors, correlated with CNS relapse risk in a multivariate analysis. Multivariate logistic regression analysis revealed that concomitant <i>MYD88 </i>L265P and <i>CDKN2A</i> loss (<i>p</i> = 0.012), <i>TET2</i> mutation (<i>p</i> = 0.037), <i>ARID1A</i> mutation (<i>p</i> = 0.010), and <i>INO80</i> (<i>p</i> = 0.002) were independently correlated with a high risk of CNS relapse after adjusting for the IPI risk groups, B symptom and cell of origin (COO). The classifier that integrated genomic risk factors was superior in predicting CNS relapse (area under the receiver operating characteristic curve [AUROC]: 0.91) compared with the IPI (AUROC: 0.77, <i>p</i> &lt; 0.001) or IPI in combination with COO classifiers (AUROC: 0.81, <i>p</i> = 0.013).</p> Conclusion <p>This study identified several genomic alterations as risk factors for CNS relapse.</p>