To assess the safety and tolerability of cyclophosphamide (CTX) 'pulse' therapy in progressive or very active multiple sclerosis (MS), we reviewed our experience in a cohort of MS patients who have been treated and prospectively followed-up in our Department since 1997. One hundred and twelve patients received intravenous CTX in monthly 'pulses' for 12 months at the dosage of 700 mg/m2 of body surface, then bimonthly for another 12 months. We evaluated the frequency and the severity of side-effects, as well as overall tolerability by the patient perspective using a visual analogue scale (VAS). Side-effects resulted in the discontinuation of therapy in 20 (18%) cases. Serious side-effects were observed in 24 patients (21.4%), most commonly definitive amenorrhea (33.3% of fertile women), hypogammaglobulinemia (5.4%), and hemorrhagic cystitis (4.5%). Malignancies were diagnosed in four (3.6%) subjects, three of whom were previously treated with azathioprine (AZA). Finally, 81.8% of the patients judged the treatment regimen as very or relatively acceptable and tolerable. Our data point to a reasonable safety and tolerability of CTX 'pulse' therapy. Further trials are needed to definitively assess the efficacy of CTX as an alternative therapeutic option for progressive or very active MS.