Correlational studies have shown associations between social class and salivary cortisol suggestive of a causal link between childhood poverty and activity of the stress-sensitive hypothalamic-pituitary-adrenocortical (HPA) system. Using a quasi-experimental design, we evaluated the associations between a family's participation in a large-scale, conditional cash transfer program in Mexico (Oportunidades, formerly Progresa) during the child's early years of life and children's salivary cortisol (baseline and responsivity). We also examined whether maternal depressive symptoms moderated the effect of program participation. Low-income households (income <20th percentile nationally) from rural Mexico were enrolled in a large-scale poverty-alleviation program between 1998 and 1999. A comparison group of households from demographically similar communities was recruited in 2003. Following 3.5 years of participation in the Oportunidades program, three saliva samples were obtained from children aged 2-6 years from intervention and comparison households (n=1197). Maternal depressive symptoms were obtained using the Center for Epidemiologic Studies-Depression Scale (CES-D). Results were that children who had been in the Oportunidades program had lower salivary cortisol levels when compared with those who had not participated in the program, while controlling for a wide range of individual-, household- and community-level variables. Reactivity patterns of salivary cortisol did not differ between intervention and comparison children. Maternal depression moderated the association between Oportunidades program participation and baseline salivary cortisol in children. Specifically, there was a large and significant Oportunidades program effect of lowering cortisol in children of mothers with high depressive symptoms but not in children of mothers with low depressive symptomatology. These findings provide the strongest evidence to date that the economic circumstances of a family can influence a child's developing stress system and provide a mechanism through which poverty early in life could alter life-course risk for physical and mental health disorders.