Dehydroepiandrosterone (DHEA) may help prevent heart disease in men. To test the hypothesis that DHEA might exert its effects by enhancing endogenous fibrinolytic potential, a double-blind, placebo-controlled study was conducted that assessed the effects of DHEA administration on plasma plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (tPA) antigen. Eighteen men received 50 mg DHEA orally and 16 men received a placebo capsule thrice daily for 12 days. Serum DHEA-sulfate and plasma PAI-1 and tPA antigen were measured before and after treatment. In the DHEA group, serum DHEA-sulfate (from 7.5 +/- 1.2 micromol/L to 20.2 +/- 1.5 micromol/L (P < 0.0001), androstenedione (from 2.6 +/- 0.2 nmol/L to 4.0 +/- 0.4 nmol/L; P < 0.005) and estrone (from 172 +/- 21 pmol/L to 352 +/- 28 pmol/L; P < 0.005) increased, whereas plasma PAI-1 (from 55.4 +/- 3.8 ng/mL to 38.6 +/- 3.3 ng/mL; P < 0.0001) and tPA antigen (from 8.1 +/- 1.9 ng/mL to 5.4 +/- 1.3 ng/mL; P < 0.0005) decreased. In the placebo group, serum DHEA-sulfate declined slightly from 8.0 +/- 3.3 micromol/L to 7.3 +/- 3.4 micromol/L (P < 0.05), but no other measured steroid changed. Plasma PAI-1 and tPA antigen did not change in the placebo group. These findings suggest that DHEA administration reduces plasma PAI-1 and tPA antigen concentrations in men.