The responsiveness to diethylstilbestrol (DES) and estramustinephosphate (EMP) of human peripheral blood lymphocytes to T-cell mitogens has been investigated in vitro and in vivo. EMP demonstrated potent inhibition of both Con A- and PHA-induced lymphocyte proliferation in vitro, while it had no detectable effects when given to patients with cancer of the prostate. DES reduced the response to Con A in vitro, but had only marginal effects on PHA-induced mitogen response. In contrast, the response to Con A was unaltered, while the response to PHA was significantly diminished after DES therapy in patients with prostatic cancer. This effect, however, was only seen when high doses of DES not included in conventional regimen were given. The proliferative response to T-cell mitogens in patients with prostatic cancer was not affected by serum source in the assay, indicating the absence of humoral factors able to inhibit mitogen response in these patients.