OBJECTIVE: To evaluate the effectiveness of methotrexate (MTX), which works not only as an immunosuppressant, but also as a potent antiinflammatory agent, as an alternative therapeutic option for patients with severe calcium pyrophosphate deposition disease (CPDD) who fail to respond to standard therapy with nonsteroidal antiinflammatory drugs and/or glucocorticoids. METHODS: We analyzed, in 2 university hospitals in Switzerland, consecutive patients with CPDD that was resistant to classic treatment and were subsequently treated with MTX. Before and after initiation of MTX therapy, we quantified the frequency of pseudogout attacks, pain intensity, the number of swollen and tender joints, and inflammatory biomarkers. Clinical and biologic side effects of MTX and patients satisfaction with MTX treatment were also evaluated. RESULTS: The study included 5 patients treated with low dosages of MTX (5-20 mg/week). The mean followup time with MTX was 50.4 months (range 6-81 months). All patients reported an excellent clinical response, with marked improvement within a mean period of 7.4 weeks. A significant decrease in pain intensity (P < 0.0001), swollen and tender joint counts (P < 0.0001), and frequency of attacks was observed. The biomarkers of inflammation decreased markedly when systematically analyzed (3 patients). No significant side effects were reported. CONCLUSION: This study suggests that MTX could be a valuable therapeutic option for severe CPDD that is refractory to conventional therapy.