Duodenal adenocarcinoma is a rare digestive cancer, often diagnosed at a late stage and harbours a poor prognosis. The arrival of immunotherapy has changed the prognosis of many neoplasia, including digestive adenocarcinomas with MSI-H status. Hereby, we describe three cases of MSI-H locally advanced duodenal adenocarcinoma who received neoadjuvant treatment with a PD1 inhibitor, pembrolizumab. A partial metabolic and endoscopic response was observed in all patients after 2 cycles. Duodenopancreatectomy was performed at the end of treatment (4–6 cycles), and anatomopathological analysis demonstrated pathological complete response in all patients. Our case series paves the way for prospectively exploring neoadjuvant immunotherapy in duodenal MSI-H adenocarcinoma and raises the question of organ sparing surgery in case of complete clinical response as observed in gastric and colo-rectal adenocarcinomas. •Duodenal adenocarcinoma is rare cancer with poorly defined standard therapies.•Immune checkpoint inhibitors have changed management of MSI-H tumours.•Neoadjuvant immunotherapy may lead to pathological complete response.•Our observation paves the way to further explore organ sparing surgery.