The effect of chlorpromazine (CLZ) on the graft vs. host reaction (G.vs.H.r.) induced by the injection of parental immunocompetent cells to F1 hybrids was studied. Rats of one parental strain were immunized with 3 X 10(7) splenic nucleated cells from the other parental strain. The injection of 3 X 10(6) and 6 X 10(6) nucleated cells obtained from the spleen of these previously immunized rats to 21-day-old F1 hybrids induced a typical G.vs.H.r. The degree of the G.vs. H.r. was estimated 10 days after the injection of the parental cells by the splenic index (S.I.) and histological studies of the spleen. The administration of CLZ (30 mg/kg/day i.p. during 10 days) either to the donor or to the host inhibited the G. vs.H.r. The effect of CLZ was partially antagonized by the simultaneous administration of Bromocriptine (10 mg/kg/day i.p.) to F1 hybrids. An effect similar, although quantitatively smaller to that of CLZ was caused by the injection of Prolactin (Pro) 100 I.U./kg/day, i.p. to F1 hybrids. None of these drugs modified neither the lymphatic structure nor the S.I. of hybrids not inoculated with lymphoid cells. The rectification of the functions number of injected cells vs. S.I. allowed us to apply the statistical method of covariance to the different treatments used and to establish the degree of significance of the modifications produced by the drugs. In contrast to the profound inhibition of the G.vs.H.r. obtained when CLZ was administered to previously immunized donors, the effect of this drug was minor if the treatment was performed in nonimmunized donors. Splenic cells obtained from rats previously immunized with the other parental strain were incubated in vitro during two hours with different concentrations of CLZ (10(-6), 10(-5) and 10(-4) M) or Pro (15,30,50,75,100,200 and 500 ng/ml). This treatment did not modify the capacity of these cells to induce G.vs.H.r. when injected into F1 hybrids. We postulate that the inhibitory action of CLZ on the G.vs.H.reaction is mediated, at least in part, by the capacity of this drug to increase the plasmatic levels of PRO. The effect of CLZ and PRO is observed mainly in lymphoid clones in expansion because of the stimulation by histocompatibility antigens.