The mitochondrial genotype 5178 cytosine/adenine (5178 C > A) within the NADH dehydrogenase subunit-2 gene (ND2) was proved to associate with longevity and predispose resistance to adult-onset diseases. This study aimed to confirm the interactive effects between ND 25178 C > A and clinical risk factors on the susceptibility of essential hypertension in Chinese general population. The relationship between the ND2 5178 C > A variation and the risk of hypertension was investigated in 817 hypertensives and 821 matched normotensives. The interactive effects between ND2 5178 C > A and clinical risk factors were evaluated. The ND2 5178 A allele was more frequent in normotensives than in hypertensives (32.64% vs. 24.24%; adjusted OR: 0.62, 95% CI: 0.49-0.79, P = 1.3 × 10- 4). After stratification, the significant association between ND2 5178 C > A and hypertension was found only in current smokers (OR: 0.44, 95% CI: 0.31-0.62), but not in non-current smokers (p <  0.01 for interaction). Smoking status (OR: 1.51, 95% CI: 1.11-2.06) and high triglycerides (OR: 1.57, 95% CI: 1.10-2.24) were found independently associated with hypertension only in carriers of 5178 C allele but not in carriers of 5178 A allele. In conclusion, ND2 5178 A allele could confer a lower risk for essential hypertension in Chinese by the interaction with smoking status. The higher risk of hypertension imposed by smoking and high TG may be altered by ND2 5178 A allele.