The nitric oxide produced by endothelial nitric oxide synthase (eNOS) plays a pivotal role in protecting the arterial wall from damages and atherosclerosis. The T–786C, the 27-bp repeat in intron 4, and the E298D eNOS gene polymorphisms were studied in 715 Brazilian patients (447 Caucasian- and 268 African-Brazilians) who underwent coronary angiography. The −786C frequency was increased in coronary artery disease (CAD) cases with significant lesions (≥50% luminal obstruction) when compared with lesion-free controls; this difference was detected in smokers but not in nonsmokers, both in Caucasian- (p = 0.011) and African-Brazilians (p = 0.005). The interaction between−786C carriers and smoking was an independent CAD predictor (OR: 2.9, 95% CI: 1.4–5.9; p = 0.003) in multiple logistic regression. The 298D mutation frequency was also higher among CAD cases (p = 0.036) in African-Brazilian smokers, but this effect was not independent from other variables in the regression model. Though not associated with CAD, the 4-repeat allele combined with different T–786C alleles showed protective and susceptible effects in Caucasian-Brazilian smokers. The −786C/4-repeat/298E haplotype frequency was higher (p = 0.020), whereas −786T/4-repeat/298E was lower (p = 0.023) in these cases. These results showed a smoking-dependent effect of the T–786C eNOS polymorphism on CAD in both Caucasian- and African-Brazilians. Additionally, the haplotype analysis revealed different eNOS haplotypes associated with protection and susceptibility to the disease.