Objective: To evaluate the effects of mitoxantrone (Mx) in progressive multiple sclerosis (MS) on MRI. Methods: A total of 194 patients with worsening relapsing-remitting or secondary progressive MS were treated with Mx 12 mg/m2 (n = 34), Mx 5mg/m2 (n = 40), or placebo (n = 36) at 3-month intervals IV over a 2-year period. In preselected MRI centers unenhanced and Gd-enhanced MRI scans were performed at month (M) 0, 12, and 24 in a non-randomized subset of 110 patients and nonselected for MRI criteria. The primary MRI outcome measure was the total number of MRI scans with positive Gd enhancement per group. Results: Twelve mg/m2 Mx failed to reach a significant difference from placebo as measured by the primary MRI outcome at month 12 (p = 0.431) and 24 (p=0.065). Secondary MRI outcome measures: 5 mg/m2 Mx influenced favorably the number of Gd-enhancing lesions only at month 24 (p = 0.004), but not at month 12 (p = 0.095). Twelve mg/m2 Mx reduced the number of T2-weighted lesions at month 24 (p = 0.027) and showed a positive trend at month 12 (p = 0.069), but not 5 mg/m2 Mx. The number of active MR lesions showed a strong trend toward reduction in the 12 mg/m2 Mx group only at month 24 (p = 0.054). All comparisons are vs placebo, and unadjusted for baseline incidence. Conclusions: In the MIMS trial 12 mg/m2 Mx does not reduce the number of MRI scans with positive Gd enhancement at month 12 and 24 vs placebo. Results of secondary MRI outcome measures are suggestive of a positive impact of 12 and 5 mg/m2 Mx on some of the Gd enhanced and unenhanced MRI measures as expected from other Mx MRI studies in the past. Methods: A total of 194 patients with worsening relapsing-remitting or secondary progressive MS were treated with Mx 12 mg / m2 (n = 34) , Mx 5 mg / m2 (n = 40), or placebo (n = 36) at 3-month intervals IV over a 2-year period. In preselected MRI centers unenhanced and Gd-enhanced MRI scans were performed at month , 12, and 24 in a non-randomized subset of 110 patients and nonselected for MRI criteria. The primary MRI outcome measure was the total number of MRI scans with positive Gd enhancement per group. Results: Twelve mg / m2 Mx failed to reach a Significant difference from placebo as measured by the primary MRI outcome at month 12 (p = 0.431) and 24 (p = 0.065). Secondary MRI outcome measures: 5 mg / m2 Mx influenced favorably the number of Gd-enhancing lesions only at month 24 (p = 0.004), but not at month 12 (p = 0.095). Twelve mg / m2 Mx reduced the number of T2-weighted lesions at mon The number of active MR lesions showed a strong trend toward reduction in the 12 mg / m2 Mx group only (p = 0.027) and showed a positive trend at month 12 (p = 0.069), but not 5 mg / m2 Mx. at month 24 (p = 0.054). All comparisons are vs placebo, and unadjusted for baseline incidence. Conclusions: In the MIMS trial 12 mg / m2 Mx does not reduce the number of MRI scans with positive Gd enhancement at month 12 and 24 vs placebo. Results of secondary MRI outcome measures are suggestive of a positive impact of 12 and 5 mg / m2 Mx on some of the Gd enhanced and unenhanced MRI measures as expected from other Mx MRI studies in the past.