Background and objective The association between few common genetic variants on chromosomal region 9p21.3 and myocardial infarction has been recently identified by genome-wide association studies. In the present study we sought to replicate the association of five 9p21.3 single nucleotide polymorphisms (SNPs) with early-onset myocardial infarction and we investigated the influence of the best tag SNP on the reoccurrence of cardiovascular events during long-term follow-up. Methods The Italian genetic study of early-onset myocardial infarction is a nationwide prospective study involving 1842 patients hospitalised for a first myocardial infarction before the age of 45 years followed up for cardiovascular events. Genotyping was performed using a Sequenome MassARRAY platform. Results All the five 9p21.3 genetic variants (rs10116277, rs1333040, rs2383206, rs10757278, and rs133049) were significantly associated with early-onset myocardial infarction (p Conclusions The 9p21.3 genetic variant rs133040 predicts the need for coronary artery by-pass surgery and for percutaneous revascularisation during long-term follow-up. Therefore, the rs1333040 9p21.3 genetic variant influences a clinical outcome that is related to the progression of coronary atherosclerosis.