The aim of this study was to evaluate the efficacy of fludarabine treatment in patients suffering from refractory rheumatoid arthritis. Four patients affected by refractory seropositive rheumatoid arthritis underwent treatment with fludarabine for 6 months. The drug was administered intravenously at a dose of 25 mg the first month in a single infusion, and then monthly for 5 months at a dose of 25 mg for 3 consecutive days. All four patients obtained no clinical benefit from the treatment; moreover, inflammation indices worsened and the prednisone dosage was increased during the trial, in spite of a significant fall in CD4+ T cells. In our experience low-dose fludarabine is not useful in the treatment of refractory rheumatoid arthritis.