The relations between habitual physical activity (PA), fibrinogen gene polymorphisms and plasma fibrinogen were investigated in 191 postmenopausal women. Subjects who reported PA at least 4 times/week had lower fibrinogen level (3.19 g/l; 95% CI 3.10; 3.27) than women reporting PA 2-3 times/week (3.43 g/l; 3.29; 3.58) or sedentary subjects (3.64 g/l; 3.33; 3.94). There were no differences in plasma fibrinogen across the alpha-fibrinogen (RsaI, TaqI) or beta-fibrinogen (MnlI, BclI, HindIII) genotypes, the frequencies of which were in a Hardy-Weinberg equilibrium. An interaction between RsaI, which was in complete linkage disequilibrium with TaqI, and PA on plasma fibrinogen was observed, even after adjustments for BMI, smoking and medication (p = 0.024). Among women homozygous for the common RsaI allele, the physically most active had lower fibrinogen level (p <0.001) compared to the physically less active subjects. These results suggest that, in postmenopausal women, the relation between physical activity and plasma fibrinogen is modulated by genetic variation in the alpha-fibrinogen gene.