INTRODUCTION: The current treatment approach of high-grade non-Hodgkin lymphoma (NHL) relies to a large extent on anthracycline-based regimens yielding cure rates in ∼ 65 - 75% of patients. Despite being highly effective, these regimens are associated with significant long-term toxicity with a cumulative 10-year incidence of cardiovascular disease of 22%. Moreover, for the 25 - 35% of patients who fail first-line therapy there has been very little progress in terms of salvage regimens over the past 15 years. Re-treatment with anthracyclines-based regimens was, until now, not an option given the extensive cardiac toxicity of these agents. Pixantrone dimaleate (Pixantrone) is a novel anthracycline-like drug that offers an interesting alternative for the treatment of aggressive NHL. AREAS COVERED: This article provides an overview of treatment-related cardiac toxicity in NHL, the pharmacology of Pixantrone and the evidence supporting its use in NHL. EXPERT OPINION: Pixantrone is a potential alternative agent with a favorable safety profile for the treatment of relapsed and refractory NHL patients. It might benefit from combinations strategies and further development in the elderly and frail population.