We assessed the interactive effect of genetic polymorphisms and exercise training on fibrinolysis in 50 - 75 yr old men (n = 17) and women (n = 28). Subjects had tissue plasminogen activator (t-PA) antigen levels and activity and plasminogen activator inhibitor-1 (PAI-1) activity measured before and after 6 mo of endurance-exercise training. Subject's DNA was typed for the PAI-1 4 G/5 G and t-PA I/D variants. Baseline PAI-1 activity, t-PA activity, and t-PA antigen levels were not different among PAI-1 or t-PA genotype groups. Overall, exercise training did not change PAI-1 activity (- 0.43 +/- 0.81 IU/mL, p = NS), increased t-PA activity (0.37 +/- 0.16 IU/mL, p = 0.02), and decreased t-PA antigen levels (- 0.88 +/- 0.20 ng/mL, p < 0.001). Although the differences in changes with training were not significant among genotype groups, significant t-PA antigen level improvements were evident only in PAI-1 4 G allele carriers and significant t-PA activity increases only in PAI-1 4 G homozygotes. t-PA genotype affected the training-induced t-PA antigen level improvements (p = 0.033) after covarying for gender and baseline t-PA antigen levels, with the smallest and largest reductions in the D homozygotes and I/D heterozygotes, respectively. These findings could have important treatment implications for the use of exercise training to reduce CV disease and thrombotic risk in older men and women.