BACKGROUND: Controversy exists regarding the association between autism spectrum disorder (ASD) in children whose mother had labour epidural analgesia for their birth, as the few existing investigations have reported mixed findings. OBJECTIVE: This study aims to evaluate the possibility of an association in our heterogeneous population. DESIGN: A retrospective population-based cohort study. SETTING: Vaginal deliveries that took place between the years 2005 and 2017 at Soroka University Medical Center, a tertiary referral hospital in Israel, and a follow-up on the incidence of ASD in the children. PATIENTS: A hundred and thirty-nine thousand, nine hundred and eighty-one labouring patients and their offspring. MAIN OUTCOME MEASURES: The incidence of children diagnosed with ASD (both hospital and community-based diagnoses) was compared based on whether their mothers had received labour epidural analgesia during their labour. A Kaplan-Meier survival curve compared cumulative incidence of ASD. A Cox proportional hazards model was used to control for relevant confounders. RESULTS: Labour epidural analgesia was administered to 33 315 women. Epidural analgesia was more common among high-risk pregnancy groups (including pregnancies complicated with diabetes mellitus, hypertensive disorders, intrauterine growth restriction, and oligohydramnios; P  < 0.001). In a Cox proportional hazards model, the association between epidural analgesia during labour and ASD in the children lost statistical significance following adjustment for confounders such as maternal age, gestational age, hypertensive disorders, diabetes mellitus, and ethnicity [adjusted hazard ratio = 1.13, 95% confidence interval (CI), 0.96 to 1.34, P  = 0.152]. CONCLUSION: In our population, after adjusting for confounders, epidural analgesia is not independently associated with autism spectrum disorder in the children. These findings enhance our knowledge regarding the safety of epidural analgesia and enable patients to make informed decisions about their pain relief techniques during labour.