To verify whether the outcome in placebo-treated MS patients actually corresponds to that expected on the basis of the natural history and pretrial evolution of the disease, we here review the results of clinical trials conducted according to a placebo-controlled, randomized design, regardless of the experimental therapy used. The frequency of relapse in remitting-relapsing patients decreases during follow-up, and disability in progressive cases increases more slowly than before enrollment. These data should be borne in mind when evaluating the impact of experimental drugs on the natural course of the disease.