We wanted to assess whether intravenous immunoglobulin G (IVIG) decreases disease activity on MRI in relapsing MS. Previous trials of IVIG in relapsing-remitting MS demonstrated a reduction of acute relapses, but these studies did not include MRI. We treated 26 patients in a randomized, double-blind, crossover study of IVIG 1 g/kg daily or placebo on 2 consecutive days every month during two 6-month treatment periods. The primary end point was the number of gadolinium-enhancing lesions on monthly serial MRI. Secondary efficacy variables were the occurrence of exacerbations, clinical neurologic ratings, total MS lesion load on T2-weighted MRI, and multimodal evoked potentials. Eighteen patients completed the entire trial; eight patients did not. Twenty-one patients completed the first treatment period and at least two MRI examinations in the second treatment period and were included in the intention-to-treat analysis. On serial MRI, we observed fewer enhancing lesions per patient per scan during IVIG treatment (median, 0.4; range, 0 to 9.3) than during placebo treatment (median, 1.3; range, 0.2 to 25.7; p = 0.03). During IVIG treatment, 15 patients were exacerbation free compared with only 7 on placebo (p = 0.02). The total number of exacerbations in the IVIG period was 11 and in the placebo period, 19 (not significant). None of the remaining secondary efficacy measures were significantly different between the two treatment periods. The number of adverse events, in particular eczema, was significantly higher during IVIG therapy than during placebo treatment. These results suggest that IVIG treatment is beneficial to patients with relapsing MS.