The purpose of this study was to explore the association between colds, depressive symptoms during pregnancy and offspring congenital heart disease (CHD). A 1:2 matching case-control study was conducted in Northwest China. Information was gathered by a structured questionnaire and was reviewed by investigators on the spot. Multivariate logistic regressions and nonlinear mixed effect model were performed. 614 cases and 1228 controls were available in this study. After adjusting for potential confounders, the colds during the entire pregnancy were associated with increased risk of offspring CHD (OR = 1.44(1.12-1.85)). Similarly, there was a higher depression score in CHD group than the control group (OR = 1.89(1.48-2.41)). In addition, the women with both colds and higher depression scores had a higher risk of offspring CHD (OR = 2.72(1.87-3.93)) than their counterparts with only colds (OR = 1.48(1.04-2.09)) or with only higher depression scores (OR = 1.94(1.37-2.74)). The combined effects were significant in the multiplication model (OR = 2.04(1.47-2.83)) but not in the additive model (S = 1.40(0.70-2.81), AP = 0.19(-0.15-0.53) and RERI = 0.55(-0.54-1.64)). In conclusion, the colds and depressive symptoms during pregnancy were found associated with increased risk of offspring CHD and we found for the first time that there existed a statistically multiplying interaction effect of colds and depression on increasing risk of offspring CHD.