We have previously reported cross-sectional data on an interaction effect between physical activity and alpha-fibrinogen RsaI polymorphism on fibrinogen in postmenopausal women. In the present controlled randomised study, we investigated the role of the RsaI polymorphism in determining the response of fibrinogen to long-term regular exercise. Middle-aged men (n = 140), randomly selected from the population registry, were randomised into an exercise or a reference group for a 3-year low intensity exercise intervention. Complete data were available in 125 men. The RsaI restriction enzyme detects threonine (Thr) to alanine change in the fibrinogen alpha codon 312. Anaerobic ventilatory threshold increased by 4%, but decreased by 2% in the exercise and reference groups, respectively. Mean fibrinogen did not decrease in either study group. However, in the exercise group, individual changes in anaerobic threshold explained 48% of the variance in fibrinogen changes in the Thr homozygotes. Our data offer a new aspect of beneficial effects of regular physical exercise on risk factors for coronary heart disease.