The PRISMS (Prevention of Relapses and Disability by Interferon-1a Subcutaneously in Multiple Sclerosis) trial was a doubleblind, randomized, multicenter, phase III, placebo-controlled study of interferon-1a in 560 patients from 22 centers in 9 countries with clinically definite or laboratory-supported relapsing-remitting multiple sclerosis. The patients were randomized to receive recombinant interferon-1a (Rebif), 22 g (6 mIU), 44 g (12 mIU), or placebo, given subcutaneously, three times weekly for 2 years. All patients underwent biannual proton density/T2-weighted magnetic resonance imaging scans to determine the overall magnetic resonance imaging disease activity and burden of disease, and a cohort of 205 patients had 11 initial monthly proton density/T2-weighted and gadolinium-enhanced/T1-weighted magnetic resonance imaging scans. Over the 2 years, the placebo group showed a progressive median increase in burden of disease of 10.9%, whereas the 22-g group and 44-g group showed median decreases of 1.2% and 3.8%, respectively. The number of T2 active lesions and percentage of scans showing T2 activity on the biannual scans were also significantly reduced in both treatment groups compared with placebo, with a clear dose-effect favoring the 44-g dose over the 22-g dose. In the subgroup undergoing initial monthly scanning, this reduction in activity became statistically significant 2 months after the start of treatment. These results provide strong, objective evidence to support the positive clinical results of reduction in relapses and delay in disease progression. In addition, they also demonstrate a significant dosage effect, favoring the 44-g dose.