This study reports on the feasibility of using intrathecal methotrexate (ITMTX) in treatment unrespon- sive multiple sclerosis (MS) patients with progressive forms of the disease. A retrospective, open-label, chart review analysis was conducted following patients (n = 121) with MS for up to eight treatments given every 8–11 weeks. Patients were considered for ITMTX treat- ment if they were unresponsive to or intolerant of FDA- approved treatments. There was a 1 year follow-up after their eighth or last treatment (if discontinued earlier). Patients underwent neurological assessments and expanded disability status scale (EDSS) evaluations. No serious adverse effects were noted during the study period. In 87 secondary progressive MS patients, EDSS scores were stable or improved in 89%, with significantly improved mean EDSS post-treatment compared to baseline (P = 0.014). Of 34 primary progressive patients, EDSS scores were stable in 82%, with no significant progression in EDSS post-treatment compared to baseline. ITMTX may have a beneficial role in progressive forms of MS and is well tolerated with no serious adverse events.