Background/Objective: Congenital hyperinsulinism (CHI) is a rare, heterogeneous disease with transient or persistent hypoglycemia. Histologically, focal, diffuse, and atypical forms of CHI exist, and at least 11 disease-causing genes have been identified. Methods: We retrospectively evaluated the treatment and outcome of a cohort of 40 patients with non-focal, persistent CHI admitted to the International Hyperinsulinism Center, Denmark, from January 2000 to May 2017. Results: Twenty-two patients (55%) could not be managed with medical monotherapy (diazoxide or octreotide) and six (15%) patients developed severe potential side effects to medication. Surgery was performed in 17 (43%) patients with resection of 66% to 98% of the pancreas. Surgically treated patients had more frequently K ATP-channel gene mutations (surgical treatment 12/17 vs conservative treatment 6/23, P =.013), highly severe disease (15/17 vs 13/23, P =.025) and clinical onset '30 days of age (15/17 vs 10/23, P =.004). At last follow-up at median 5.3 (range: 0.3-31.3) years of age, 31/40 (78%) patients still received medical treatment, including 12/17 (71%) after surgery. One patient developed diabetes after a 98% pancreatic resection. Problematic treatment status was seen in 7/40 (18%). Only 8 (20%) had clinical remission (three spontaneous, five after pancreatic surgery). Neurodevelopmental impairment (n = 12, 30%) was marginally associated with disease severity (P =.059). Conclusions: Persistent, non-focal CHI remains difficult to manage. Neurological impairment in 30% suggests a frequent failure of prompt and adequate treatment. A high rate of problematic treatment status at follow-up demonstrates an urgent need for new medical treatment modalities.