BACKGROUND: Acinar cell carcinoma (ACC) of the pancreas is a rare neoplasm, accounting for 1% of all pancreatic neoplasms. There remains a lack of data regarding the use of systemic therapy in this disease. We present a series of 40 consecutive cases of ACC of the pancreas treated at Memorial Sloan-Kettering Cancer Center, with an emphasis on evaluation of activity of new therapeutic agents. METHODS: Patients reviewed at our institution from January 2000 through January 2011 were identified from an institutional database with prior institutional review board approval. Pathology was confirmed in all cases as ACC or a closely related entity. RESULTS: Forty patients were identified; 29 were male (73%). The median age at diagnosis was 65 years (range, 16-87 years). The median overall survival (OS) time for patients with localized, resectable disease was 56.9 months and the OS time for patients with metastatic ACC (n = 18) was 19.6 months. Six patients with metastatic or recurrent ACC had a partial response to chemotherapy and five patients had stable disease for ≥6 months on systemic chemotherapy. Clinical observation was made of a patient with ACC and hereditary nonpolyposis colorectal cancer and a patient with ACC and a BRCA1 germline mutation. CONCLUSIONS: ACC is moderately chemoresponsive to agents that have activity in pancreatic adenocarcinoma and colorectal carcinoma. A potential association between germline mutations in DNA mismatch repair genes and ACC warrants further evaluation.