Adhesion molecules play important roles in immune reactions and inflammatory processes and may constitute attractive targets for immunomodulatory approaches. In this study, blocking mAbs against a series of adhesion molecules were tested for their therapeutic effect on developing arthritis in a mouse model. MAbs were given for a period of 4 weeks at the time of exspected incidence of visible disease symptoms, i.e. 4 weeks after priming with collagen type II. A significant reduction of incidence down to values of 13% and 29% of the controls was obtained with mAbs against CD44 and a₄-integrin, respectively, during an observation time of 13 weeks. MAbs against CD4 and LFA-1 resulted only in weaker, non-significant effects or a delay in the incidence. MAbs against other molecules including L-selectin, ICAM-1 or VCAM-1 were not effective. The development of antibodies against collagen type II, collagen type I, proteoglycans and the immunogen, bovine collagen type II was affected by mAb treatment to a different extent. In this case, the anti CD4 mAb was the most effective, followed by the anti α₄-antibodies in most cases, whereas anti CD44 showed less clear effects on the development of humoral responses. In a skin delayed type hypersensitivity model analyzed for comparision, mAbs against LFA-1/ICAM-1 and α₄-integrin showed the largest effects on ear swelling. These data show that mAbs against several adhesion molecules are able to block selectively distinct aspects of immune reactions, and that CD44 and α₄-integrins could be promising targets for an immunotherapy of rheumatoid arthritis with receptor-interfering agents.