This prospective cohort study aimed to assess incidence and etiology of adult-onset epilepsy in previously seizure-free Atahualpa residents aged ≥ 20 years. Persons with adult-onset epilepsy occurring over 5 years were identified from annual door-to-door surveys and other overlapping sources. Those who emigrated or declined consent were excluded at the administrative censoring date of the last survey when these subjects were interviewed. Persons who died and those who developed incident epilepsy were censored at the time of these outcomes. Poisson regression models adjusted for demographics, education, alcohol intake, and the length of observation time, were used to estimate annual adult-onset epilepsy incidence rate ratio and cumulative incidence. Systematic neuroimaging screening was offered to participants to get insights on the etiology of epilepsy. Individuals enrolled in this cohort (N = 1,480) contributed to 6,811.6 years of follow-up. Seventeen developed incident adult-onset epilepsy, for an annual incident rate of 249.2 per 100,000 persons-year (95% CI: 130.7–367.7). Cumulative incidence was 1,245.9 per 100,000 persons (95% CI: 653.7–1,838.3) after a mean of 4.6 (SE: 0.06) years of follow-up. Six persons with incident epilepsy had neurocysticercosis (35%). Individuals with neurocysticercosis were six times more likely to develop adult-onset epilepsy than those without this disease (IRR: 6.01; 95% CI: 2.16–16.7), after adjusting for relevant covariates. The attributable fraction of incident adult-onset epilepsy due to neurocysticercosis was 30.9% (95% CI: 25.6–46.2%). This rural Ecuadorian population has a high incidence of adult-onset epilepsy, with neurocysticercosis being an important contributory cause.