SUMMARYTrichosanthin (Tk), a plant protein isolated from a Chinese medicinal herb, was shown in our previous experiments to suppress mitogenic, antigenic and allogeneic responses of human lymphocytes. Two non‐toxic pathways, the CD8‐dependent and the CD8‐independent, were identified as being involved in inducing the suppression. In this communication, we report that, in a subgroup of healthy subjects, only the CD8‐dependent pathway was found to operate. In cell cultures from the other subjects, removal of CD8 cells from the culture did not diminish the suppression, implying that the down‐regulatory function of the CD8 cells was not expressed in the presence of Tk. Two types of subject, CD8 mediators (M+) (CD8‐dependent pathway operating) and non‐mediators (M−) (CD8‐independent pathway operating), were thus distinguishable. A ‘mediation index’(MI) was calculated as MI (%) = RR of CD8‐depleted cell culture ‐ RR of non‐CD8‐depleted cell culture. Of 68 unrelated subjects tested, 21 (30.9%) could be classified as M+, with a mean ‘mediation index’ of 13.4±4.0, while 47 (69.1%) were M−, with a mean MI of −5.6±4.3 (t= 17.2,P<0.001). The M+and M−groups exhibited an essentially non‐overlapping bimodal distribution of MI. Among the 40 Caucasoids in the panel, nine of 14 M+subjects were HLA‐DR7, DQ2 (χ2= 14.652,Pc= 0.00084). The two DR7‐DQ3 panel members, however, were M−, suggesting that DQ2 might be associated with M+. Segregation patterns in two families revealed