Mitoxantrone is a recently approved drug for patients with secondary progressive multiple sclerosis (SPMS). However, cardiac side effects limit Mitoxantrone use in SPMS and its lifetime cumulative dose should not exceed 140 mg/m2. Additionally, Mitoxantrone is contraindicated for use in SPMS patients with a baseline left ventricular ejection fraction (LVEF) of < or = 50%. The goal of this study was to monitor LVEF more frequently than ordinarily recommended since experience with Mitoxantrone use in SPMS patients is limited. An unexpected decline in LVEF in one of the SPMS patients being treated with Mitoxantrone prompted further investigation into this finding. In our clinic, 47 patients on Mitoxantrone were followed prospectively; 28 of 47 patients had received a minimum of three doses and underwent a repeat LVEF evaluation prior to their fourth dose of Mitoxantrone. Of these 28 patients, five of 28 (17.8%) had a significant decline in LVEF from baseline. It is suggested that more stringent cardiac monitoring guidelines than current Food and Drug Administration (FDA) recommendations be used to avert potential cardiac complications in SPMS patients on Mitoxantrone.