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<b><i>Background:</i></b> Increasing studies have reported that 5′-nucleotidase cytosolic II (<i>NT5C2</i>) has a strong relationship with coronary heart disease (CHD) development. This study was designed to examine the relationship between <i>NT5C2</i> polymorphisms and CHD in the Chinese Han population. <b><i>Methods:</i></b> We studied 501 CHD patients and 496 healthy controls from the Second Affiliated Hospital of Hainan Medical University in Hainan Province, China. Four single nucleotide polymorphisms (SNPs) in <i>NT5C2</i> were selected and genotyped using Agena MassARRAY technology. Odds ratios and 95% confidence intervals were calculated using logistic regression after adjusting for age and gender. Stratification analysis was performed by age and gender in all individuals; we especially investigated the effects of <i>NT5C2</i> SNPs on hypertension and diabetes among CHD patients. <b><i>Results:</i></b> rs2148198 of <i>NT5C2</i> was strongly associated with an increased risk of CHD (allele: <i>p</i> = 0.045; codominant: <i>p</i> = 0.007; additive: <i>p</i> = 0.016). Stratified analysis revealed that rs2148198 was associated with increased CHD risk in individuals aged ≤61 years and males. For CHD patients, rs2148198 significantly affected the risk of hypertension and diabetes (<i>p</i> &#x3c; 0.05). Further, rs79237883 of <i>NT5C2</i> was associated with decreased susceptibility to hypertension in multiple genetic models for individuals with CHD (allele: <i>p</i> = 0.007; codominant: <i>p</i> = 0.001; dominant: <i>p</i> = 0.001; additive: <i>p</i> = 0.008). <b><i>Conclusion:</i></b> This study reports the association of <i>NT5C2</i> gene variants and CHD susceptibility in the Chinese Han population. Especially, <i>NT5C2</i> rs2148198 was significantly associated with CHD risk in the subgroups of males, hypertension, and diabetes.