Azathioprine (Aza) has been proposed in the treatment of multiple sclerosis (MS) since 1971 and continues to be used in MS Clinical Centres. Recent data, suggesting its efficacy in reducing MRI lesion load and in refractory IFN-treated MS patients, has renewed interest in this drug. Its therapeutic index over other immunosuppressive agents is generally considered favourable, but concerns about a possible risk of malignancy have limited its use. On the other hand, the occurrence of unexpected adverse events (AEs) in clinical trials in recent years has aroused the interest in the safety profile of the drugs. No systematic review of AEs in patients affected by MS is available. The aim of this study is to review the safety profile of the drug in patients affected by MS, in order to support a correct management of these patients in the clinical practice. The controlled and observational clinical studies published between 1971 and 2007 have been included. The AEs have been registered in ad hoc form and the frequency has been calculated. The risk of cancer and toxicity on reproductive function has been also considered. Gastrointestinal complaints and leukopenia are the most frequent AEs of Aza therapy in MS, occurring in more than 10% of the patients, while infections, allergy, anaemia, thrombocytopenia and pancytopenia are common (>1%-<10%). Pancreatitis is not common (>0.1%-<1%). Most of them are easily managed by dosage adjustment or therapy interruption. The cancer risk increases with the treatment duration and cumulative dose. No data on reproductive toxicity in MS treated with Aza are available. The safety profile of Aza is acceptable, if strategies for management of expected AEs are adopted, following dosage and treatment duration indications, and if long-term monitoring to evaluate the risk of cancer is warranted.