In young patients, the accumulative burden of traditional cardiovascular risk factors may not be as significant as in an older population. Genetic risk factors were suggested to have a role in the early development of myocardial infarction (MI). However, data about the association between polymorphisms in heart disease-related genes and the early onset of a first MI are limited. In the present study, age at onset of a first MI was related to individual single-nucleotide polymorphisms in each of 18 prespecified candidate genes in a cohort of 814 patients enrolled in the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) Study. Multivariate regression analysis showed in patients who had the high-risk genotypes of paraoxonase 1 (PON1) Q192R and endothelial nitric oxide synthase (eNOS) E298D that ages at onset of a first MI were 1.8 (p = 0.02) and 3.5 years (p = 0.02) earlier than in noncarriers of the genotypes, respectively. Consistently, high-risk genotypes of the PON1 Q192R and eNOS E298D polymorphisms were significantly associated with onset of a first MI at age <50 years (adjusted odds ratio 1.70, p = 0.005, adjusted odds ratio 2.15, p = 0.01, respectively). In conclusion, our findings suggest that high-risk genotypes of the PON1 Q192R and eNOS E298D polymorphisms are independently associated with a significantly earlier occurrence of coronary events.