Antidepressant drugs are reported to cause alterations in blood glucose homeostasis in adults with diabetes mellitus. We report a patient with persistent congenital hyperinsulinism (CHI) who developed recurrent hypoglycaemia following fluoxetine therapy. This 15-year-old girl was initially managed with diazoxide therapy. She developed troublesome hypertrichosis, which affected her quality of life adversely. Diazoxide was then slowly weaned and stopped with the introduction of octreotide, to which she responded well. Subcutaneous lanreotide (long-acting somatostatin analogue) was subsequently commenced (30 mg, once monthly) as injecting octreotide multiple times a day was proving to be difficult for the patient. The continuous blood glucose monitoring on monthly lanreotide injections revealed good glycaemic control. Six months later, she developed depression due to psychosocial problems at school. She was started on fluoxetine by the psychiatry team. She subsequently developed recurrent symptomatic hypoglycaemic episodes (blood glucose <3.5 mmol/L) and fluoxetine was discontinued, following which the hypoglycaemic episodes resolved within a week. Fluoxetine has been associated with hypoglycaemia in patients with diabetes mellitus. We report, for the first time, hypoglycaemia secondary to fluoxetine in a patient with CHI.