Cyclophosphamide (Cyc) is an alkylating agent used to treat malignancies and autoimmune diseases, such as lupus nephritis, rheumatoid arthritis and immune-mediated neuropathies. Over the past 40 years, Cyc has also been applied to treat multiple sclerosis (MS) and the effective stabilisation of rapidly progressive forms of MS has been demonstrated in several studies. Cyc has a dose-dependent bimodal effect on the immune system. High doses have been demonstrated to induce an anti-inflammatory immune deviation (i.e., suppression of T helper 1 and enhancement of T helper 2 activity), affect CD4CD25(high) regulatory T cells and establish a state of marked immunosuppression. Data from the literature suggest that Cyc is particularly indicated in the treatment of young MS patients, suffering from a very active inflammatory disease characterised by frequent relapses and rapid accumulation of disability and displaying gadolinium-enhancing lesions on brain magnetic resonance. The most common Cyc-based therapeutic protocol applied in MS consists of monthly intravenous pulses for 1 year followed by bimonthly pulses for the second year, with or without prior infusion of corticosteroids. This protocol is usually well tolerated by the patients. Indeed, most of the side effects (mild alopecia, nausea and vomiting, cystitis) are dose dependent, transient and completely reversible. Definitive amenorrhoea is observed only in older female patients (aged > 40 years). Cyc has a safety and efficacy profile similar to that of mitoxantrone and can be used in patients whose disease is not controlled by IFN-beta or glatiramer acetate. Short course (6-12 months) of Cyc therapy can precede the initiation of immunomodulatory treatment in selected patients with an aggressive MS onset.