The aim of the present study was to detect the combined effect of negative life events and the norepinephrine transporter (NET) gene on the development of major depression (MD) in a Chinese population. We recruited 388 unrelated patients affected with MD and 388 healthy controls in this study. The score of 32 was used as a cut-off value for grouping the negative life events into the severe and moderate forms using the Life Events Scale (LES). SNPs including rs2242446 and rs5569 of the NET gene were genotyped. The chi-square (χ2) test showed allelic association for the T-182C polymorphism (χ2 = 6.46, corrected P = 0.011) and also showed genotypic association (χ2 = 6.87, corrected P = 0.034). Multifactor dimensionality reduction (MDR) showed that the interaction between the rs2242446-rs5569 combination and negative life events had a CV consistency of 10 and PE of 0.3487. Compared with those having both T-G-MN combination used as reference group, we found that the OR scaled up from 1 to 7.39 (95%CI 3.40-16.06) in the C-A-SN group. The present study suggests that the combined effect of rs2242446 and rs5569 in the NET gene could modify the response to the negative life events in triggering MD.