Definitive evidences proving the clinical efficacy of Cyclophosphamide (CFX) and Cyclosporine A (CSA) in Multiple Sclerosis are still lacking. To verify the effectiveness of those therapeutic interventions in modifying the clinical evolution of the disease, we performed a systematic review of clinical trials in MS using CFX e CSA, by Medline and Embase research. Data contained in each article were collected by using a computerized data form, considering the following items: study design; clinical features of patients; outcome measures; results' evaluation; evaluation of study liability as suggested by drop-outs and withdrawals; side effect evaluation and toxicity data. For each trial and for the various comparisons, the overall odds ratio was calculated. Since the revised studies were found to be heterogeneous both in terms of outcome measures and in terms of type of analysis performed, we considered as events of interest: a) the percentage of patients worsened one or more points at Kurtzke'e EDSS; b) relapse frequency. Briefly, the meta-analysis suggest that treatment with CSA as compared to placebo, is able to significantly reduce the likelihood of worsening only at 6 months; CFX reduces the likelihood of disease progression significantly at 6 months and at 12 months as compared to placebo, but different treatment schedules do have different clinical effectiveness.