Several studies have reported lower focal demyelination and inflammatory activity in primary progressive multiple sclerosis (PPMS) than in relapsing-remitting MS (RRMS). However, very little is known about possible differences in damage and distribution that may occur within lesions visible on magnetic resonance imaging in the 2 forms of the disease. To evaluate differences in spatial distribution and structural damage of focal demyelinating lesions in patients with PPMS and RRMS. We acquired conventional magnetic resonance and magnetization transfer images in 24 PPMS and 36 RRMS patients (matched for sex, age, and disease duration) and 23 healthy sex- and age-matched controls. In each participant, we measured T2- and T1-weighted lesion volumes and magnetization transfer ratios in lesional and nonlesional brain tissues. The spatial distribution of focal demyelination was assessed using T2- and T1-weighted lesion probability maps in each patient group. Voxel-based procedures were performed. University hospital. Patients with PPMS had greater disability than those with RRMS, with 70% of PPMS patients and 11% of RRMS patients having relevant motor symptoms. The T1- and T2-weighted lesion volumes were higher in PPMS than in RRMS patients (P < .001). T1- and T2-weighted lesion probability maps showed that the maximum probability for lesions was higher in PPMS (peak probability, 45% and 29%, respectively) than in RRMS (peak probability, 33% and 19%, respectively) patients and was localized in the corona radiata. Voxelwise analysis of lesional magnetization transfer ratios gave overlapping results. Differences in cerebral pathologic involvement exist between RRMS and PPMS and contribute to variations in clinical disability.