This study examined the effect of myeloid differentiation primary response gene 88 mutation L265P (MYD88) and/or cluster of differentiation 79B gene mutation Y196 (CD79B) (MYD88/CD79B) on central nervous system (CNS) relapse in 270 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Over a median follow-up of 6.65 years, 20 patients experienced CNS relapse. Fifty-five (20%) patients had MYD88/CD79B mutations, and these mutations were significantly associated with an increased risk of CNS relapse in univariable analysis. The overall median time to CNS relapse was 11.5 months, with relapses continuing beyond 2 years in patients harbouring MYD88/CD79B mutations. These patients had 2- and 6-year cumulative CNS relapse rates of 10.9% and 18.1% respectively. Among patients classified as having low or intermediate risk according to the CNS-International Prognostic Index (CNS-IPI), those with MYD88/CD79B mutations exhibited higher CNS relapse rates than those without these mutations (18.8% vs. 1.2%). In contrast, patients with high risk showed high CNS relapse, regardless of the mutation status, suggesting heterogeneous mechanisms underlying CNS relapse. In conclusion, the results of this study suggest that MYD88/CD79B mutations may serve as a predictive marker for CNS relapse in DLBCL, although further validation in additional cohorts is warranted.