The highly variable clinical course and the lack of a direct measurement of disease activity have made evaluation of experimental therapies in multiple sclerosis (MS) difficult. Recent studies indicate that clinically silent lesions can be demonstrated by magnetic resonance imaging (MRI) in patients with mild relapsing-remitting MS. Thus, MRI may provide a means for monitoring therapeutic trials in the early phase of MS. We studied 12 patients longitudinally for 12 to 21 months with monthly gadolinium (Gd)-enhanced MRIs. The data have been used to identify the most effective design of a clinical trial using Gd-enhanced lesions as the outcome measure. Frequent ( > 1/mo) Gd-enhancing lesions were observed in 9 of the 12 patients, indicating that the disease is active even during the early phase of the illness. The frequency of the lesions was not constant; there was marked fluctuation in lesion number from month to month. However, the magnitude of the peak number of lesions and the frequency of the peaks varied among patients. Because of this variability, the most effective use of Gd-enhancing lesions as an outcome measure in a clinical trial was a crossover design with study arms of sufficient duration to allow accurate estimation of lesion frequency. Monitoring Gd-enhancing lesions may be an effective tool to assist in the assessment of experimental therapies in early MS.