A possible mechanism to explain the suppression of mitogen-induced lymphocyte proliferation in vitro by histamine-stimulated mononuclear cells was investigated. In initial experiments, the inhibitory action of histamine-induced suppressor factor (HSF) on lymphocyte proliferation was documented to be reduced by the addition of indomethacin (1 microgram/ml). Moreover, the addition of exogeneous PGE2 (10(-7)-10(-8) M) to mononuclear cell cultures reconstituted HSF activity in the presence of indomethacin. In order to ascertain the nature of the target cell responding to HSF, control and suppressor supernatants were incubated with human lymphocytes or monocytes (5 X 10(6) cells/ml) for 24 hr. Following incubation, the supernatants were assayed for their content of prostaglandin E2, F2 alpha, and thromboxane B2. Monocytes (but not lymphocytes) incubated with supernatants containing HSF increased their production of prostaglandin E2, F2 alpha, and thromboxane B2 by 169, 53, and 49%, respectively. Suppressor supernatants were generated with histamine or an H-2 agonist (dimaprit) and chromatographed by gel filtration on Sephadex G-100. The elution profiles for the factor(s) inducing suppression of lymphocyte proliferation (25-40,000 daltons) and augmenting PGE2 production (25,000 daltons) overlapped but were not identical. Collectively, these data suggest that HSF-mediated inhibition of lymphocyte proliferation may occur in part through the augmented production of prostaglandins and/or thromboxane B2 by human monocytes.