In the current study, we show that MYD88 S257 phosphorylation is required for optimal NF-κB activation in DLBCL and that a phosphomimetic (S257D) mutant promotes IRAK1 phosphorylation, NF-κB activity, and cell growth with a similar efficacy as the oncogenic MYD88 L265P mutant and, moreover, can rescue DLBCL cells addicted to this oncogenic driver. Here, MYD88 is linked to diffuse large B-cell lymphoma.