Rheumatoid arthritis is a chronic progressive disease causing substantial morbidity and mortality for which current treatments are largely unsatisfactory. Over the past 20 years we have developed a novel therapeutic approach based on the intra-articular administration of rifamycin. The published studies on rifamycin therapy of rheumatoid arthritis and other chronic arthritic disorders, mainly from our group, are reviewed. Our results indicate that intra-articular rifamycin is effective against active synovitis and can profitably be combined with any basic therapy with slow-acting antirheumatic drugs. There is good evidence that the development of new erosions can be prevented or delayed by this treatment and that the balance between side-effects (mainly local pain) and antiarthritic activity is very favourable in the long term. Our observations have led us to hypothesize a possible systemic effect of rifamycin injected multilocally in peripheral joints; we believe that the available data deserve further investigation by independent researchers.