Background High numbers of persons with nodding syndrome and other forms of epilepsy were reported to occur in onchocerciasis endemic regions of South Sudan but an epilepsy prevalence survey was never performed. Methods In May 2018, a door-to-door household survey was conducted in 8 study sites, including 44 villages in an onchocerciasis endemic area in Maridi County. Onchocerciasis-associated epilepsy (OAE) was defined as ≥2 seizures without any obvious cause, starting between the ages of 3-18 years in previously healthy persons who had resided for at least 3 years in the onchocerciasis endemic area. Findings A total of 2,511 households agreed to participate in the study, corresponding to 17,652 individuals. An epilepsy screening questionnaire of 5 questions identified 799 persons suspected to have epilepsy (4.5%); in 736 (96.1%) of the 766 seen by a clinical officer or medical doctor the diagnosis of epilepsy was confirmed. Adding 38 persons not seen, but with a positive answer to a combination of screening questions to have epilepsy, 774 (4.4%) persons had epilepsy. Epilepsy prevalence was highest in the 11-20 age group (10.5%). The median age at first seizure was 10 years (IQR: 7-14); 66 persons with epilepsy (PWE) developed their first seizures in the year preceding the survey (annual incidence=373.9/100.000). OAE criteria were met by 85.2% of PWE. In 45.4% there was a history of nodding seizures. Neurocysticercosis cannot explain the high epilepsy prevalence because there are no pigs kept in the area. Independent risk factors for epilepsy included male gender, belonging to a permanent household, belonging to a farming family, and living in a village bordering the Maridi River. Only 7209 (40.8%) of the total population took ivermectin in 2017. Interpretation Urgent action is needed to prevent children in Maridi County from developing OAE by strengthening the onchocerciasis elimination program. Funding: European Research Council (ERC) grant 671055 Declaration of Interest: No conflict of interest declared. Ethical Approval: Ethical approval was obtained from the ethics committee of the Ministry of Health of the Republic of South Sudan and from the ethics committee of the University of Antwerp, Belgium. The study aims and procedures were explained to all participants in the language of their choice, and signed or finger-printed informed consent was obtained from participants, parents or carers, and assent obtained from adolescents (age 12–18 years). All personal information was encoded and treated confidentially.