Using the Early Childhood Longitudinal Study–Birth Cohort (ECLS-B), a nationally representative data set, we examined the extent to which mothers of preschool children with and without the diagnosis of an Autism Spectrum Disorder (ASD) reported stress and depressive symptoms prior to and following diagnosis of ASD. At 4 years, approximately 100 children were parent-identified as diagnosed with ASD. Mothers of children with ASD at 9 months and 4 years had significantly higher incidence of depressive symptoms and stress than mothers of typically developing children. Mothers of children with ASD experienced higher levels of depressive symptoms than mothers of children with disabilities, but the difference was not statistically significant. Using linear regression, a within-group comparison of depressive symptoms of mothers of children with ASD indicated no differences based on child gender, ethnicity, number of children in the family, or partnership status. Implications are presented.