To evaluate the contribution of the 46C>T polymorphism of the Factor XII (FXII) gene to risk for coronary heart disease (CHD) in the West of Scotland Coronary Prevention Study (WOSCOPS) of men with high cholesterol.WOSCOPS is a primary prevention trial that demonstrated the effectiveness of pravastatin in reducing morbidity and mortality from CHD. FXII is a protein of the contact system that plays a key role in both coagulation and fibrinolysis. Elevated activated FXII (FXIIa) levels have been previously associated with CHD. Plasma FXIIa levels are strongly determined by a 46C>T polymorphism in the FXII gene.441 CHD cases and 990 controls were genotyped. The frequency of TT homozygotes was 8.3% in controls and 11.8% in cases (P=0.04). When compared with the CC+CT group (after adjustment for age, blood pressure, BMI, fibrinogen and lipid levels) the TT genotype was an independent risk factor for CHD (OR 1.48 95% CI 1.01-2.17), an effect that was only significant in the pravastatin group (OR 1.95 95% CI 1.09-3.47) and not in the placebo group (OR 1.20, 95%CI 0.72-2.02). Compared with risk in the placebo group as a whole (reference group), and after adjustment for other risk factors, men with the CC or CT genotype, but not the TT genotype showed a significant benefit from pravastatin treatment (OR, respectively, 0.61 (0.46-0.81) and 0.56 (0.40-0.79) compared with 1.10 (0.64-1.96). In a subgroup of these men, subjects with the TT genotype had, as expected, baseline levels of FXIIa that were 50% lower than those with the CC genotype, with CT subjects having intermediate levels (PT polymorphism is associated with a high risk of CHD in men with high cholesterol. We hypothesise that reduced fibrinolysis in these men, as a consequence of lower plasma FXIIa, may be the mechanism leading to higher risk, and that pravastatin treatment may enhance this effect.