Abstract Objective To estimate the risk of ischaemic stroke associated with antidopaminergic antiemetic (ADA) use. Design Case-time-control study. Setting Data from the nationwide French reimbursement healthcare system database Système National des Données de Santé (SNDS). Participants Eligible participants were ≥18 years with a first ischaemic stroke between 2012 and 2016 and at least one reimbursement for any ADA in the 70 days before stroke. Frequencies of ADA reimbursements were compared for a risk period (days -14 to -1 before stroke) and three matched reference periods (days -70 to -57, -56 to -43, and -42 to -29) for each patient. Time trend of ADA use was controlled by using a control group of 21 859 randomly selected people free of the event who were individually matched to patients with stroke according to age, sex, and risk factors of ischaemic stroke. Main outcome measures Association between ADA use and risk of ischaemic stroke was assessed by estimating the ratio of the odds ratios of exposure evaluated in patients with stroke and in controls. Analyses were adjusted for time varying confounders (anticoagulants, antiplatelets, and prothrombotic or vasoconstrictive drugs). Results Among the 2612 patients identified with incident stroke, 1250 received an ADA in the risk period and 1060 in the reference periods. The comparison with the 5128 and 13 165 controls who received an ADA in the same periods yielded a ratio of adjusted odds ratios of 3.12 (95% confidence interval 2.85 to 3.42). Analyses stratified by age, sex, and history of dementia showed similar results. Ratio of adjusted odds ratios for analyses stratified by ADA was 2.51 (2.18 to 2.88) for domperidone, 3.62 (3.11 to 4.23) for metopimazine, and 3.53 (2.62 to 4.76) for metoclopramide. Sensitivity analyses suggested the risk would be higher in the first days of use. Conclusions Using French nationwide exhaustive reimbursement data, this self-controlled study reported an increased risk of ischaemic stroke with recent ADA use. The highest increase was found for metopimazine and metoclopramide.