The aim of this study was to investigate the association of the Bcl I beta-chain fibrinogen polymorphism with the risk of acute myocardial infarction (AMI) and its relationship with fibrinogen levels in the Italian population. We studied 102 AMI patients, selected within the framework of the GISSI-2 trial, who had a familial history of arterial thrombosis (at least one first-degree relative suffering from AMI or stroke before 65 years) and 173 control subjects (with neither AMI nor personal or familial history of arterial thrombosis). All subjects were Italian. Patients showed fibrinogen levels higher than control subjects. There was a highly significant difference in allele frequency in cases versus control subjects, the B2 allele frequencies being respectively 0.28 versus 0.17 (P = .002). In multivariate analysis, adjusted for sex, age, smoking habits, and history of hyperlipidemia, hypertension, or diabetes, the (B1B2 + B2B2) genotype was associated with a higher risk of AMI (odds ratio 2.4, 95% confidence interval, 1.2 to 4.6). The Bcl I genotype was also associated with fibrinogen levels, independently of gender and smoking habits, the (B1B2 + B2B2) subjects showing the highest levels in both cases and control subjects. The difference in fibrinogen levels between cases and control subjects was significantly influenced by the genotype (significant interaction, P = .042). The B2 allele of the Bcl I polymorphism in the beta-chain of the fibrinogen gene is a new factor associated with the risk of familial AMI through its association with fibrinogen levels. These data provide evidence for a causal role of fibrinogen in familial AMI.