Background Air pollution exposure in childhood is associated with greater incidence and exacerbation of asthma, particularly in children whose parents report high levels of psychological stress. However, this interaction has not been completely elucidated in pregnancy. Objective To examine whether the association between prenatal exposure to particulate matter no larger than 2.5 μm in diameter (PM2.5) and wheeze in children is modified by prenatal stress. Methods Mexican women were recruited during pregnancy (N = 552). Residential prenatal daily exposure to PM2.5 was estimated using a satellite-based spatiotemporally resolved prediction model and averaged over trimesters. Maternal stress was indexed by maternal negative life events (NLE) score (range 0–11) ascertained during mid to late pregnancy. NLE scores were dichotomized at the median as low (NLE score ≤ 3) and high (NLE score > 3) stress. Reports of ever wheeze and wheeze in the past 12 months (current wheeze) for children were obtained using the International Study of Asthma and Allergies in Childhood survey at 48 months. The association between prenatal PM2.5 and wheeze was analyzed using a modified Poisson regression and stratified by low vs high stress. Results Greater PM2.5 exposure during the first trimester was associated with increased risk of current wheeze among children with mothers reporting high prenatal stress (relative risk 1.35, 95% confidence interval 1.00–1.83, per interquartile range increase 3.8 μg/m3) but not among those reporting low stress (relative risk 0.84, 95% confidence interval 0.61–1.16, per interquartile range increase 3.8 μg/m3; P for interaction =.04). Conclusion Increased prenatal stress enhanced the association between PM2.5 exposure in early pregnancy, and child wheeze at 48 months of age. It is important to consider chemical and nonchemical stressors together to more comprehensively characterize children's environmental risk.