The transplantable human prostatic tumor model (PC-82) in nude mice was used to evaluate the indirect and possibly direct effects of estrogens on the growth of prostatic tumor tissue. High (pharmalogical) doses of plasma estradiol (E2) were achieved in tumor-bearing mice by using E2-containing Silastic implants of different lengths. In comparison with the situation in men, in mice much higher concentrations of circulating E2 (exceeding 3 nmol/liter) were necessary to attain (near)-castrate levels of plasma testosterone (T). Treatment of tumor-bearing mice with a high dose of E2 resulted in tumor growth arrest and a subsequent decline of the tumor volume, which equals the effects of castration. No evidence was found that either of the two doses of E2 applied had any additive inhibitory effect on tumor growth when compared to castration alone. It was inferred from these findings that in the PC-82 tumor model, estrogens, rather than having a direct effect on the tumor tissue, mainly act indirectly by their suppressive effect on T secretion in the host animal. A different and unexpected result was obtained in castrated tumor-bearing mice treated with a combination of E2 and T. With both doses of E2 this type of treatment led to a smaller increase of the tumor volume compared with mice receiving T only, the result of the high dose being statistically significant. This antagonistic effect of the two steroids on the PC-82 tissue was paradoxically associated with a sharp increase of nuclear androgen receptor levels and a higher concentration of dihydrotestosterone in the tumor tissue. Plasma and tissue concentrations of T appeared to be unaltered. The present study of the PC-82 prostate tumor shows that only by careful monitoring of plasma steroid levels in tumor-bearing mice can conclusions about the effectiveness of hormonal treatment regimens, such as estrogen therapy, be drawn.