Objective: This paper examines the school readiness of a regional cohort of prenatally methadone-exposed children across five outcome domains and examines factors contributing to impairment risk. Method: A sample of 100 children born to women in methadone maintenance treatment and 110 randomly identified non-methadone-exposed children were studied from birth to age 4.5 years. At 4.5 years, children underwent comprehensive assessment of their physical/motor development, social-emotional skills, approaches to learning, language, and cognitive functioning. Predictors of children’s overall school readiness were examined, including the extent of prenatal substance exposure and social risk, maternal mental health, infant clinical factors, and the total score from the Home Observation Measurement of the Environment (HOME) scale administered at 18 months. Results: Methadone-exposed children had higher rates of delay/impairment across all outcome domains (ORs 4.0–5.3), with 72% impaired in at least one domain. Multiple problems were also common, affecting 48% of methadone-exposed children compared with 15% of control children. The mean number of school readiness domains impaired increased with increasing prenatal substance exposure (rate ratio [RR] =1.05 [1.01–1.11]), higher social risk (RR = 1.35 [1.20–1.53]), male sex (RR = 1.69 [1.27–2.25]), and lower HOME scores indicating a poorer quality postnatal environment (RR = 0.96 [0.94–0.99]). Conclusions: Children born to opioid-dependent mothers are at high risk of impaired school readiness, with problems in multiple domains common. Impaired school readiness was associated with greater maternal substance use, higher social risk, male sex, and lower quality caregiving environments.