Context Pancreatic Neuroendocrine Tumors are overall rare tumors with a poor prognosis. Treatment options for high grade pancreatic neuroendocrine tumors are limited especially for those with progressive disease. Everolimus, an oral inhibitor of mammalian target of rapamycin, has been approved for the treatment of patients with low- or intermediate-grade advanced pancreatic neuroendocrine tumor. Case report Herein we present a case of a 52-year-old patient who has been diagnosed with Stage IV, high-grade large-cell neuroendocrine carcinoma of the pancreas with liver and lung metastases. The patient first treated with cisplatin and etoposide for six cycles; then his disease progressed after a year of observation. As a result, he was treated with capecitabine and temozolomide as a second line treatment for seven cycles until he experienced significant toxicity and the treatment was stopped. Subsequently, the treatment with everolimus and octreotide long-acting release combination was stared. Our patient achieved a long-term survival benefit for 52 months and prolonged clinical response to third line everolimus plus octreotide for more than 28 months. Conclusion This case demonstrates activity of the combination of everolimus plus octreotide long-acting release, and warrants further evaluation in large cell neuroendocrine tumors.