Background: Autism spectrum disorder (ASD) is a severe psychiatric disorder of childhood that entails severe difficulties in verbal, non-verbal communication, language development, repetitive and limited patterns of behaviors, and obsessive resistance to small changes in familiar surroundings. Objectives: to assess the role of epidemiological, clinical and psychiatric determinants as risk factors of ASD. Methods: A case control study was conducted on 72 ASD children attending psychiatric outpatient clinic, and 72 healthy children. Their caregivers completed a questionnaire about risk factors for ASD. Then they underwent complete assessment of mental age using Stanford-Binet intelligence scale, childhood autism rating scale to outline severity of ASD in cases and exclude presence of autistic features in controls. Results: There is a statistically significant difference between both groups regarding parents’ education, fathers’ age at conception time, family history of psychiatric disorders, history of ovulation induction, hypertension during pregnancy, folic acid supplementation during 1st trimester of pregnancy, use of anti D, history of postnatal hypoxia, admission to NICU, and diet type. A significant difference between the two groups concerning reaction to others and delayed developmental milestones was found. About 63% and 58% had severe autism and mild to severe mental retardation respectively. Paternal age, positive family history of psychiatric diseases, postnatal hypoxia significantly increased risk of ASD. Folic acid supplementation during 1st trimester of pregnancy significantly decreased ASD risk. Conclusion: Family history of psychiatric disorders, advanced fathers’ age at time of conception, and postnatal hypoxia were significant risk factors. Folic acid supplementation during the 1 st trimester is a significant protector.