In a long-term prospective study following 5,626 patients with rheumatoid arthritis for 25 years, methotrexate use was associated with a substantial reduction in risk of death, after adjustment for individual propensity for methotrexate use (adjusted HR 0.30; 95% CI 0.09–1.03). The reduction in mortality risk was evident only in those who used the therapy for >1 year, but higher cumulative exposure did not translate into increased survival.