We monitored 56 patients with chronic progressive multiple sclerosis (MS) who participated in a clinical trial of weekly, low-dose oral methotrexate with annual gadolinium-enhanced MRIs of the brain (Gd + MRI). Not of these patients had clinical exacerbations during the 8 months preceding study entry. We also monitored 35 of the patients with serial Gd + MRIs every 6 weeks for 6 months. We observed a treatment effect, measured by absolute change in T2-weighted total lesion area (T2W-TLA), in the cohort that completed 6-week scans. We found change in T2W-TLA in this cohort to be significantly related to sustained change in performance on the nine-hold peg test but not to sustained change on the Expanded Disability Status Scale. Gadolinium enhancement of lesions on 6-week and annual scans was uncommon. Prestudy exacerbation frequency appears to be an important consideration in designing future clinical trials in patients with secondary and primary progressive MS.