A positive family history (FH) of coronary artery disease (CAD) is considered an independent risk factor for developing CAD. However, the natural history, coronary angiographic findings and prognosis of patients with a positive FH developing first acute myocardial infarction (AMI) are not well defined. A cohort of 2,690 consecutive patients with first AMI from two prospective nationwide surveys conducted during 1996 and 1998 in all coronary care units operating in Israel was studied. Baseline characteristics, hospital course, management and outcome of 405 patients with first AMI and a positive FH were compared with 2,285 controls without a positive FH. Coronary angiograms of patients with and without a positive FH were reviewed and compared. Patients with a positive FH were younger (53 vs. 64 years), more often male, current smokers and patients with hyperlipidemia, but less often patients with diabetes or hypertension than patients without a positive FH. Patients with a positive FH developed heart failure during hospital stay less frequently. Thrombolytic therapy was similarly administered to both groups. During the hospital stay, coronary angiography, percutaneous coronary intervention or coronary artery bypass grafting were more frequently performed in patients with a positive FH. The coronary anatomy and the extent of the CAD were similar in patients with and without a positive FH. Crude and covariate-adjusted mortality rates were significantly lower in patients with a positive FH than in patients without a positive FH on day 30 (2.2 vs. 9.6%, p < 0.001; odds ratio 0.50, 95% confidence interval 0.22–0.99) and at 1 year (3.5 vs. 14%, p < 0.001; hazard ratio 0.58, 95% confidence interval 0.42–0.80). Patients with a positive FH developed their first AMI more than 1 decade earlier in comparison to those without such a history. The extent of their coronary disease is similar to the older patients without a positive FH. The better prognosis of patients with a positive FH is mostly explained by their younger age.