Abstract Introduction Few studies evaluated risk factors for primary ventricular fibrillation (VF) before reperfusion during a first acute myocardial infarction (AMI). Important parameters such as kalemia, blood pressure (BP) and heart rate (HR) at presentation were rarely considered. Furthermore, potential differences according to the time elapsed between symptoms onset and VF onset have never been investigated. Objectives to evaluate predictors of primary VF in the PREDESTINATION (PRImary vEntricular fibrillation and suDden dEath during a firST myocardIal iNfArcTION) study cohort also differentiating between early (<60 min from symptoms onset) and late (>60 min) VF. Early VF is more likely to cause sudden death (SD) before medical services arrival. Patients and Methods PREDESTINATION is a prospective, multicenter, case–control (1:2 age– and sex–matched) study enrolling patients aged 18–80 years with a first AMI, either complicated (cases) or not (controls) by primary VF before reperfusion. Results 1478 patients were analysed: mean age was 59 years, 83% were male, 36% cases. The multivariate analysis (logistic regression) on the whole population (c–statistic= 0.74) identified 8 independent predictors of primary VF: atrial fibrillation as presenting rhythm (OR 4.61), kalemia ≤3.5 mEq/L (OR 2.8), HR at presentation ≥90 bpm (OR 2.25), first–degree family history of SD (OR 2.08), anterior infarct site (OR 1.54), physical inactivity (OR 1.59), systolic BP at presentation (OR 0.98 for each mmHg), and first–degree family history of coronary artery disease/myocardial infarction (OR 0.71). The time elapsed between symptoms onset and VF was known for 405 cases (184 early and 221 late VF). There were 6 predictors of early VF, with loss of significance of physical inactivity and of family history of coronary artery disease/infarction, and an increase in the OR of family history of SD to 2.85 (95% CI: 1.6–5.08), and in the c–statistic of the model to 0.80. Among the 6 predictors of late VF, on the other hand, anterior site of AMI and family history of SD were not confirmed (c–statistic of the model 0.7). Conclusions The present study identified 8 independent predictors of primary VF. First–degree family history of SD is a powerful independent predictor of early VF, but not of late VF, suggesting that genetic predisposition plays a determining role only in early–onset VF cases and therefore the advisability of a specific genetic investigation in these patients.