Solid-pseudopapillary neoplasm of the pancreas (SPN) is a rare neoplasm that is typically indolent in nature. Surgical resection is the preferred method of treatment and often associated with a good prognosis. Local invasion and metastasis have been reported in a small subset of patients. Currently, there are limited data on the molecular mutation profile of invasive and metastatic SPN. In this report, we present the case of a 38-year-old female with a locally-invasive and unresectable SPN that, despite exhaustive chemoradiotherapy, progressed to liver metastasis. Pyrosequencing of the primary pancreatic tumor antecedent to metastasis showed an uncommon EGFR mutation at L861Q in the kinase domain of exon 21. This finding, if confirmed in additional cases of metastatic SPN, would support preoperative testing for EGFR mutation analysis to detect aggressive SPNs.