We have shown in earlier studies that the isoxazol derivative, HWA 486, prevents the onset of the adjuvant disease in Lewis rats. The diminished arthritic reaction was correlated with an improved response of lymphocytes to T- and B-cell mitogens, indicating that HWA 486 may have immunomodulating activity. We have further elucidated the activity of this substance in mice and compared it to that of cyclophosphamide (Cy), prednisolone (Pr) and cyclosporin A (CsA). After five days of oral treatment the HWA 486 pattern of response differed from each of the three immunosuppressive agents. Both Cy and Pr inhibited the formation of plaque forming cells (PFC) to sheep red blood cells (SRBC), antibody production to SRBC, mitogen induced lymphocyte proliferation, and the PMA stimulated chemiluminescence of peritoneal lavage cells (PL-cells). CsA and HWA 486 were also inhibitory in the formation of PFC and antibodies to SRBC, yet neither substance affected the LPS induced blastogenesis. HWA 486 differs, though, from CsA in that the T-cell mitogens (Con A and PHA) were able to induce proliferation in lymphocytes obtained from animals treated with this compound. Also, the PMA-induced chemiluminescence from PL-cells was enhanced. The data indicates that HWA 486 has inhibitory activity on T-dependent B-cells, yet does not affect T-independent B-cells, and may not influence T-cell responsiveness. These findings may explain the disease modifying activity of HWA 486 in adjuvant-induced arthritic rats.