We aimed to further assess the safety and efficacy of low-dose oral methotrexate (LDOM) treatment for chronic progressive MS (CPMS). We studied 20 CPMS patients, including 16 with secondary progressive MS who had shown disease progression in the previous year. The mean follow-up was 23 months. The mean EDSS score was 6.3+/-1.1 before treatment and 6.4+/-1.1 after one year of treatment. At one year, 15 of 20 patients were still being treated, and 10 were stable. Twelve patients have completed 18 months of treatment, and eight are stable. Two patients stopped treatment because of side effects, two more because they did not perceive benefit, and one was lost to follow-up. Six patients had mild, transient increases in liver enzymes not requiring treatment interruption, and two had localized herpes zoster. Magnetic resonance imaging (MRI) performed before treatment and at one year remained unchanged in responders. We confirm that LDOM is safe in carefully selected and monitored CPMS patients. MTX is inexpensive and, given its anti-inflammatory and immunomodulatory properties, may be used as add-on therapy in non-responders to interferon beta, although hepatic toxicity may be a problem in long-term treatment.