Rheumatoid arthritis (RA) is characterized by chronic inflammation and irreversible destruction of articular cartilage and bone. Disease progression as assessed by radiographic imaging of structural joint damage is a key outcome measure in RA. Joint damage is especially rapid during early phases of RA, thus the current trend of early aggressive therapy with disease-modifying antirheumatic drugs (DMARDs). Radiographic analysis of disease progression with the novel DMARD leflunomide was compared to methotrexate and sulfasalazine in two large, placebo-controlled, randomized Phase III studies (N = 580). The results as indicated by changes in x-ray scores indicate that leflunomide and both active comparators slow disease progression significantly better than placebo (P < or = 0.01). Slowing of disease progression with leflunomide was similar to sulfasalazine at 6 months but better than methotrexate (P < or = 0.049) at 12 months. These data verify the ability of leflunomide to slow disease progression and confirm its disease-modifying potential.