BackgroundCommunity-directed treatment with ivermectin (CDTi) is used to eliminate onchocerciasis. However, despite 25 years of annual CDTi in Mahenge, Tanzania, the prevalence of onchocerciasis and onchocerciasis-associated epilepsy remained high in certain rural villages. Therefore, in 2019, bi-annual CDTi was introduced in the area. This study assessed the impact of the programme on the incidence of epilepsy in four villages.MethodologyDoor-to-door epilepsy surveys were conducted prior to (2017/18) and after (2021) implementing a bi-annual CDTi program. All household members were screened for epilepsy symptoms using a validated questionnaire, and suspected cases were examined by a medical doctor to confirm/reject the diagnosis of epilepsy. The prevalence and annual incidence of epilepsy, including nodding syndrome, were calculated with 95% Wilson confidence intervals with continuity correction. The latter was also done for CDTi coverage in 2016 and 2021.ResultsPrecisely 5,444 and 6,598 persons were screened for epilepsy before and after implementing the intervention. The CDTi coverage of the overall population was 82.3% (95%CI: 81.3–83.2%) in 2021 and sustained in both distribution rounds (81.5% and 76.8%). The coverage was particularly high in children and teenagers aged 6 to 18 years (93.2%, 95%CI: 92.1–94.2%). The epilepsy prevalence remained similar: 3.3% (95%CI: 2.9–3.9%) in 2017/18 versus 3.1% (95%CI: 2.7–3.5%) in 2021. However, the incidence of epilepsy declined from 177.6 (95%CI: 121.2–258.5) in 2015–2017 and 2016–2018 to 45.5 (95%CI: 22.2–89.7) in 2019–2021 per 100,000 persons-years. The incidence of probable nodding syndrome varied from 18.4 (95%CI: 4.7–58.5) to 5.1 (95%CI: 0.3–32.8). None of the nine incidence cases of epilepsy for which information on ivermectin intake was available took ivermectin in the year they developed their first seizures.ConclusionA bi-annual CDTi programme should be implemented in areas with high prevalence of onchocerciasis and epilepsy. High CDTi coverage among children is particularly important to prevent onchocerciasis-associated epilepsy.