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Many epidemiological studies suggest that elevated plasma fibrinogen concentrations form one of the most important independent risk factors in blood for cardiovascular disease and particularly atherosclerosis in humans. To clarify the effect of genetic factors, diets and their interactions on plasma fibrinogen concentrations, we examined plasma fibrinogen levels in four strains of mice, which differ in their susceptibility to cholesterol-induced atherosclerosis. When maintained on basal diet, two strains 129/J and C3H/HeJ exhibited a significantly higher plasma fibrinogen concentration (2.1 and 1.9 mg/ml) than C57BL/6J and BALB/C strains (1.5 and 1.4 mg/ml). The strongest and most rapid (1 week) increase of plasma fibrinogen (by all semi-synthetic diets) is observed in C57BL/6J mice, which are known to be highly susceptible to diet-induced atherosclerosis. After a period of 8 weeks an increase in plasma fibrinogen of approximately 30–50% was observed in all strains on all semi-synthetic diets. Remarkably, no increase was observed in the fibrinogen Aα- Bβ- and γ-chain mRNA levels in the liver on the same diets. These mRNA levels were even decreased by approximately 20–50% in all strains on an extremely atherogenic diet. It was found that: genetic background determines the plasma fibrinogen levels on basal diet; plasma fibrinogen levels are altered by diet; the extent of these changes depends on the genetic background: surprisingly, this increase of fibrinogen in plasma is independent of transcription; the diet-induced increase of fibrinogen was very fast in the very highly atherosclerosis-susceptible strain C57BL/6J having a low basal fibrinogen level, and very slow in the atherosclerosis-resistant strain C3H/HeJ having a high basal fibrinogen level. It might be concluded that it is the kinetics of the response of fibrinogen to diet rather than the actual level, which relates to atherosclerosis susceptibility. [Copyright &y& Elsevier]