We evaluated outcome of 235 primary treatment failure (PTF) diffuse large B-cell lymphoma (DLBCL) patients based on salvage chemotherapy regimen and putative cell-of-origin (COO). Patients were divided into two groups; group A (n = 38) received high-dose cytarabine containing regimen, either DHAP or ESHAP. Patients in group B (n = 197) received ifosfamide, carboplatin, and etoposide (ICE) +/− rituximab. No difference in overall response rates (CR + PR) was observed based on salvage chemotherapy regimen and COO. After adjustment for the presence of ultra high-risk features, overall survival of germinal center B-cell like (GCB) DLBCL patients in group A was not significantly different from survival in group B (HR 0.86, 95% CI 0.46–1.60, p =.64). Similarly, within non-GCB DLBCL cohort, survival in group A was comparable to group B (HR 0.53, 95% CI 0.20–1.44, p =.21). We did not find an outcome difference between two commonly used salvage chemotherapy regimens in patients with PTF DLBCL based on COO.