Diffuse large B-cell lymphomas (DLBCLs) can be classified into two subtypes: germinal-centre B-cell (GCB)-like and Activated B-cell (ABC)-like tumours, which are associated with longer or shorter patient overall survival, respectively. In our previous studies, we have shown that, although DLBCL tumours of GCB-like and ABC-like subtypes express similar levels of IL4 mRNA, they exhibit distinct patterns of IL-4-induced intracellular signalling and different expression of IL-4 target genes. We hypothesized that these differences may contribute to the different clinical behaviour and outcome of DLBCL subtypes. Herein, we demonstrated that IL-4 increased the sensitivity of GCB-like DLBCL to doxorubicin-induced apoptosis and complement-dependent rituximab cell killing. In contrast, IL-4 protected ABC-like DLBCL from the cytotoxic effects of doxorubicin and rituximab. The distinct effects of IL-4 on doxorubicin sensitivity in GCB-like and ABC-like DLBCL cells may be partially attributed to the contrasting effects of the cytokine on Bcl-2 and Bad protein levels in the DLBCL subtypes. These findings suggest that the different effects of IL-4 on chemotherapy and immunotherapy-induced cytotoxicity of GCB- and ABC-like DLBCL could contribute to the different clinical outcomes exhibited by patients with these two subtypes of DLBCL.