The goal of this study, including 87 rheumatoid arthritis (RA) patients, was to evaluate the long-term efficacy of leflunomide administered after methotrexate failure, as well as to determine prognostic factors for the probability of good therapeutic response. Evaluation of the response durability was the secondary aim. The probability of good therapeutic response (DAS28 reduction >1.2), analyzed as cumulative incidence, equalled 57% at 30 months. Good response occurred in the early months of therapy as well as after 24 months. In a univariate and multivariate analysis initial WBC>10 × 109/l was associated with increased response rate, while radiological stage 4 resulted in decreased chance of a good response. For patients who achieved the response, the two-year probability of therapy continuation without RA progression was 87%. We conclude that leflunomide is effective in RA patients after methotrexate failure. The therapy should be long-lasting as the response may occur late. Our results allow better selection of candidates for leflunomide treatment.