Mitoxantrone is an anthracenedione antineoplastic agent approved as an escalating immunotherapy for multiple sclerosis. Owing to structural similarity with other anthracyclines, cardiotoxicity is a severe side effect of mitoxantrone. The risk of mitoxantrone-induced cardiotoxicity in patients with multiple sclerosis increases with cumulative doses >100 mg/m(2) body surface area (BSA). However, the effect of mitoxantrone on cardiac function in the early phase of treatment with cumulative doses <100 mg/m(2) BSA is unclear. The present report concerns four patients with a temporary and considerable decrease in left ventricular ejection fraction (LVEF) and with additional echocardiographic findings of diastolic dysfunction after only one or two doses of mitoxantrone. The risk of cardiotoxicity at low doses of mitoxantrone is highlighted.