Introduction: The prognosis of patients with relapsed/refractory aggressive non-hodgkin lymphoma (R/R aNHL) remains poor with conventional immunochemotherapies. Pixantrone is an aza-anthracenedione agent designed to improve the efficacy and reduce the toxicity associated with anthracyclines and anthracenediones. In this context, we conducted a phase II trial combining pixantrone with ifosfamide, etoposide and rituximab (PIVeR) in R/R aNHL. The primary objective was to assess the efficacy measured by the overall metabolic response (OMR) rate after 2 cycles. Methods: Patients were eligible if they had a histologically proven CD20+ aNHL (de novo diffuse large B-cell lymphoma (DLBCL) or transformed low-grade NHL or grade 3B follicular lymphoma). R/R disease was defined as follows: (1) autologous stem-cell transplantation (ASCT) eligible patients who failed to achieve a CR after at least one salvage therapy, (2) patients in first relapse after ASCT or (3) patients not eligible for ASCT who failed to achieve a CR after at least one prior treatment. First response evaluation by PET-scan was performed after 2 cycles. Responders could then proceed, if eligible, to ASCT or CAR T-Cells therapies after a third optional cycle. Others responding patients were treated with four additional cycles. The study was designed in order to detect an OMR rate increase from 40% to 55%, assuming an 80% power at a 5% (1-sided) significance level using a two-stage phase II design. A total of 84 evaluable patient was expected. Results: Between March 2018 and December 2021, 74 patients were enrolled. The median age was 70 y (range 35–87). The majority of the patients had a diagnosis of de novo DLBCL (85.1%) and 43.2% were primary refractory. After 2 cycles, the OMR rate was 59.5% (90% CI = 49.2%–69.1%) with 18.9% complete metabolic response (CMR). A total of 44 patients completed the treatment. At the end of treatment, the OMR rate was 36.5% with 24.3% CMR. With a median follow-up of 16.6 mo, median PFS and OS were respectively 3.7 mo (95% CI = 2.6–5.6) and 19.2 mo (95% CI = 11.9–36.5). Three patients had an ASCT and 16 were treated with CAR T-Cells. For patients treated with CAR T-Cells, the OMR rate after CAR T-Cells was 31.3% and median OS was not reached. A total of 53 patients (71.6%) reported at least one AE. The most frequent grade 3–4 AEs were neutropenia (28.4%), thrombocytopenia (18.9%) and anemia (17.6%). Cardiac AEs occurred in 6 patients (11.3%) and 5 (9.4%) had a grade 3–4 heart failure. Serious AEs occurred in 30.9% of the patients, leading to treatment discontinuation in 3 cases. Conclusion: The primary objective of this trial was met with a high OMR rate of 59.5% after 2 cycles of the PIVeR regimen. The safety profile appeared manageable with few grade 3–4 cardiac AEs. Based on these results, the use of pixantrone in salvage treatment of R/R aNHL should be further evaluated, in particular in the context of bridging therapy before CAR T-Cells.