Treatment of murine CBA splenocytes with Vibrio cholerae neuraminidase (VCN) prior to engraftment into cyclophosphamide (CY) immunosuppressed Balb/c x CBA mice reduced the incidence of acute lethal graft-versus-host disease (GvHD) and delayed mortality in the later phase of the disease. In the same model, pretreatment of donor splenocytes with VCN also reduced splenomegaly. Engraftment of F1 mice with CBA cells was clearly demonstrated at day 30 after infusion. Treatment of spleen cells with VCN did not compromise their ability to protect mice against irradiation-induced lethality. Furthermore, enzyme treatment was found to have no adverse effects on helper (TH-) and B-cell activity or on suppressor (TS-)cell function in adoptive transfer assays. Therefore, whereas the mechanism of the effect of the VCN preparation remains to be established, it is clear that the treatment provides protection against GvHD.