Purpose Few studies of risk factors for autism spectrum disorder (ASD) have been prospective in design or investigated the role of psychosocial factors measured during pregnancy. We aimed to investigate associations between prenatal psychosocial factors - including stress, social-support, depression, and trouble paying for basic needs - and risk of ASD in offspring, as part of a multicenter prospective cohort study of more than 2,000 mother-child pairs. Methods Nulliparous women aged 18–35 years, living in Pennsylvania, USA, were interviewed during pregnancy and multiple times postpartum over the course of a 3-year period. There were 2,388 participants who completed the Screen for Social Interaction Toddler Version (SSI-T), a measure of risk of ASD, when their child was 36 months old. We investigated the association between a variety of adverse psychosocial factors experienced during pregnancy and risk of ASD in offspring at the age of 3-years, controlling for relevant confounding variables. Results There were 102 children (4.3%) who scored as at risk of ASD at 3-years. Based on multivariable logistic regression, prenatal psychosocial factors that were significantly associated with risk of ASD were low social-support and trouble paying for basic needs. Other factors associated with risk of ASD were low maternal education, maternal use of antibiotics and antidepressants during pregnancy, and having a male child. None of the pregnancy or delivery complications were associated with risk of ASD. Conclusion These findings suggest that maternal experience of adverse psychosocial factors during pregnancy may be important intrauterine exposures related to the pathogenesis of ASD.