The aim of this study was to determine the effects of the anti-CD4 monoclonal antibody (mAb) W3/25, found to be nondepleting, on the onset of rat adjuvant arthritis (AA), and, in addition, to ascertain whether depletion of CD8+ cells during the same period could interfere with those effects. Female Wistar rats in which AA had been induced were treated with W3/25 and/or OX8 (anti-rat CD8) mAb during the latency period of arthritis. W3/25 alone or in combination with OX8 prevented the inflammatory process of AA. When the protected groups were rechallenged with a second dose of Mycobacterium butyricum no arthritis was observed. Protected and nonprotected arthritic animals developed the same anti-mycobacteria antibody levels as the arthritic control group. This study indicates that a nondepleting anti-CD4 mAb can prevent AA, while CD8+ lymphocytes do not appear relevant for the development of AA and do not seem to have a regulatory role for CD4+ cells.