Few studies have examined the possible pregnancy-related risk factors for necrotizing enterocolitis (NEC)-associated deaths during infancy. Infant death due to NEC in preterm babies was identified from the US Linked Livebirth and Infant Death records between 2000 and 2004. The average number of cigarettes per day reported by the mothers who were smoking during pregnancy was classified in three categories: non-smoking, light smoking (<10 cigarettes/day) and heavy smoking (≥10 cigarettes/day). Logistic regression analyses examined the association between prenatal smoking and NEC-associated infant mortality rates with adjustment for potential confounders. Compared with non-smoking mothers, light and heavy smoking mothers have a higher risk of NEC-associated infant mortality [light smoking: adjusted odds ratio (aOR) = 1.21, 95% confidence interval (CI), 1.03-1.43; heavy smoking: aOR = 1.30, 95% CI, 1.12-1.52], respectively. Moreover, the association was stronger among white race (light smoking: aOR = 1.69, 95% CI, 1.34-2.13; heavy smoking: aOR = 1.44, 95% CI, 1.18-1.75) and female babies (light smoking: aOR = 1.31, 95% CI, 1.02-1.69; heavy smoking: aOR = 1.62, 95% CI, 1.29-2.02). Maternal smoking during pregnancy is associated with increased risks of infant mortality due to NEC in preterm babies, especially in white race and female babies.