ABSTRACT: Factor XIIIA (FXIIIA) levels are independent predictors of early prognosis after acute myocardial infarction (AMI) and the Valine-to-Leucine (V34L) single nucleotide polymorphism (SNP) seems associated with lower AMI risk. Since the long-term AMI prognosis merits deeper investigation, we performed an observational study evaluating relationships between FXIIIA residual levels, cardiovascular risk-factors, and inherited genetic predispositions. FXIIIA V34L was genotyped in 333 AMI patients and a five-year follow-up was performed. FXIIIA levels assessed at day-zero (d0) and four days after AMI (d4), and conventional risk factors were analyzed, focusing on the development of major adverse cardiovascular events (MACE). FXIIIA assessed at d0 and d4 was also an independent MACE predictor in the long-term follow-up (FXIIIAd0, Odds Ratio (OR) = 3.02, 1.79?5.1, p = 0.013; FXIIIAd4, OR = 4.46, 2.33?8.55, p = 0.0001). FXIIIAd4 showed the strongest MACE association, suggesting that the FXIIIA protective role is maximized when high levels are maintained for longer time. Conversely, FXIIIA levels stratified by V34L predicted MACE at a lesser extent among L34-carriers (Hazard Risk (HR)VV34 = 3.89, 2.19?6.87, p = 0.000003; HRL34-carriers = 2.78, 1.39?5.57, p = 0.0039), and V34L did not predict all MACE, only multiple-MACE occurrence (p = 0.0087). Finally, in survival analysis, heart failure and death differed significantly from stroke and recurrent ischemia (p = 0.0013), with FXIIIA levels appreciably lower in the former (p = 0.05). Overall, genetically-determined FXIIIA levels have a significant long-term prognostic role, suggesting that a pharmacogenetics approach might help to select those AMI patients at risk of poor prognosis in the need of dedicated treatments.