Primary mediastinal large B-cell lymphoma (PMLCL) is an aggressive non-Hodgkin lymphoma with distinct clinical and gene expression profiles. Outcomes of salvage chemotherapy and autologous stem cell transplantation (ASCT) for relapsed or refractory disease (RR) have not been well characterised. We retrospectively identified 180 consecutive RR patients (37 PMLCL and a control group of 143 DLBCL) that underwent salvage chemotherapy. The overall response rate (ORR) to salvage chemotherapy (25% vs. 48%, p = 0.01) and 2-year OS after diagnosis of RR disease (15% vs. 34%, p = 0.018) was inferior in PMLCL patients. The 2-year post-ASCT OS (67% PMLCL vs. 53%, p = 0.78) and PFS (57% PMLCL vs. 36%, p = 0.64) were similar. RR PMLCL had an inferior ORR and survival compared with DLBCL but chemosensitive PMLCL and DLBCL patients have similar outcomes post-ASCT. Strategies for PMLCL should focus on identifying poor risk patients to test novel induction and salvage strategies.