In a recent multicenter retrospective study, we analyzed the influence of prior exposure to rituximab on response rates and outcomes in 163 patients with relapsed or refractory DLBCL who received Rituximab-ESHAP (R-ESHAP) as salvage therapy with a curative purpose. In this study, prior exposure to rituximab did not have an independent effect on response rates to R-ESHAP. However, a high proportion (57.4%) of patients who had received prior rituximab treatment experienced disease relapse or progression, that translated into a significantly worse PFS (17 v 57% at 3 years) and OS (38% v 67% at 3 years) as compared with rituximab-naïve patients. This observation was independent of other prognostic factors with an impact upon these outcomes, such as disease status at R-ESHAP, age-adjusted International Prognostic Index (IPI) or response to R-ESHAP. Results of the CORAL randomised trial comparing R-ICE with R-DHAP in 396 patients with relapsed or refractory DLBCL confirmed that exposure to rituximab prior to salvage therapy is associated with a worse outcome . Rituximab naïve patients had a 83% response rate and 47% 3-year event-free survival (EFS) compared with a 51% response rate and 21% EFS for patients who had received prior rituximab treatment.