We investigated the involvement of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in the pathogenesis of heat-killed S. aureus-induced arthritis. TNF-alpha and IL-1beta peaked at 2 and 24 hr after the injection, respectively. Leukocyte infiltration within 12 hr of the inflammation was significantly inhibited (80%) by coinjection of anti-TNF-alpha mAb and IL-1 receptor antagonist (IL-1Ra) with S. aureus; however, leukocyte infiltration at 24 hr and thereafter was not inhibited by these agents. The loss of proteoglycan in S. aureus-induced arthritis was also unchanged either by anti-TNF-alpha mAb, IL-1Ra, or their combination. These results indicate that direct participation of TNF-alpha and IL-1 in the pathogenesis of S. aureus-induced arthritis may be limited to the early stage of inflammation and blocking of these cytokines did not result in diminishing the severity of inflammation. Thus, therapeutic approaches with the objective to suppress TNF-alpha and IL-1 may not be effective in the clinical treatment of gram-positive bacteria-induced arthritis.