Summary Purpose: Intractability in epilepsy is difficult to define, and little is known about its onset, course, and duration. We investigated these aspects (as well as the occurrence of intractability) during long‐term follow‐up in patients with epilepsy, focusing on possible explanations for the variation in time of onset and duration of intractability. Methods: After diagnosis, 453 patients with childhood‐onset epilepsy had a 5‐year follow‐up with regular visits and data collection. Ten years later they received a questionnaire with items concerning epilepsy, which was completed by 413 patients resulting in a mean follow‐up of 15 years. Intractability during the first 5 years was compared with that in the last year of follow‐up. Intractability was defined as having no 3‐month remission during a 1‐year period despite adequate medical treatment. Key Findings: At least 12.1% of the cohort had a period of intractability during the 15‐year follow‐up, and 8.5% were intractable in the final year. Of the patients with idiopathic etiology 4.3% had a period of intractability versus 17.0% for those with cryptogenic, and 22.6% for those with remote symptomatic etiology (p < 0.001). Other risk factors at baseline were younger age at first seizure, generalized cryptogenic/symptomatic or localization‐related symptomatic epilepsy, mental retardation, and febrile convulsions before enrollment. The cumulative risk of a period of intractability was 6.1% (95% confidence interval [CI] 3.7–8.5) at 2 years follow‐up and 8.2% (95% CI 5.4–11.0) at 5 years. The mean time to onset of intractability during the first 5 years of follow‐up was 1.6 (95% CI 1.3–2.0; median 1.0) years and the mean duration of intractability during these 5 years was 3.3 (95% CI 2.8–3.8; median 3.6) years. Fifteen patients were intractable only during the first 5 years of follow‐up (group A), and 19 subjects were intractable both during the first 5 years and the last year of follow‐up (group B). Compared with group A, group B had shorter remission and a ...