Objective: In this cross-sectional, case-controlled study, we aimed to evaluate classical and novel risk factors in young patients with coronary artery disease (CAD), and the relation between coronary risk factors and coronary lesion distribution. Methods: Fifty-three patients under age of 45 years with severe coronary artery stenosis on angiography (group A) and age matched sixty patients having normal or non-critical stenosis on coronary angiography (group B) comprised the study groups. Conventional (smoking, family history, diabetes, hypertension) and novel risk factors (lipoprotein (a), homocysteine) were compared between the groups. Moreover, the relation between risk factors, and coronary lesions distribution, including left main artery (LMA) or proximal or mid left anterior descending (LAD) artery and remaining coronary lesions was investigated. Logistic regression analysis was used to define confounding factors predicting severe CAD and coronary lesion distribution and ROC curve analysis was performed to determine the cut-off value of independent factors, which were assessed by logistic regression analysis. Results: Smoking was more prevalent in group A compared to group B. Lipoprotein (a) and homocysteine levels were also higher in group A than group B. For group A and B median (max-min) values of lipoprotein (a) were 34 (2-174) mg/dl and 38 (2-203) mg/dl (p=0.038), respectively and homocysteine levels were 12.3 (5-56.6) µmol/L and 9 (1.4-19) µmol/L (p=0.012), respectively. Smoking and homocysteine were independent predictors of severe CAD in young patients according to logistic regression analysis with an Odds ratio of 3.7 (95% CI=1.572-8.763; p=0.002) and 1.2 (95% CI=1.045-1.341; p=0.008), respectively. For predicting significant CAD the cut-off value of homocysteine was 11.6 µmol/L with a sensitivity and specificity of 53% and 77%, respectively (AUC=0.637; 95% CI=0.542-0.725; p=0.008). Within group analysis in group A patients revealed that only homocysteine was an independent predictor of LMA or proximal or mid-LAD lesion presence with an Odds ratio of 1.2 (95% CI=1.011-1.465; p=0.016). ROC curve analysis revealed a cut-off value of 12 µmol/L in predicting LMA or proximal or mid-LAD lesions with a sensitivity and specificity of 65% and 91%, respectively (AUC=0.735; 95% CI=0.594-0.850; p=0.002). Conclusion: In our study, we found that young patients with severe CAD had different risk profile with higher frequency of smoking and increased levels of lipoprotein (a) and homocysteine. While smoking status and homocysteine may be used for prediction of severe CAD in young individuals, only homocysteine predicted coronary lesion distribution in LMA and proximal or mid-LAD.