The molecular pathobiology of pancreatic cystic neoplasms is poorly understood. The aim of this study was to know the involvement of epidermal growth factor receptor (EGFR) and its downstream targets in the serous cystic neoplasms and the mucinous cystic neoplasms of the pancreas. In a total of 72 pancreatic cystic neoplasms, including 39 serous cystic neoplasms and 33 mucinous cystic neoplasms, we examined the expression of native and phosphorylated EGFR, mitogen-activated protein kinase (MAPK), and AKT by immunohistochemistry and somatic mutations in EGFR, KRAS, BRAF, and PIK3CA, by direct sequencing. We also assessed the copy numbers of EGFR transcripts and the amplification of the EGFR gene in some of the samples. We found that EGFR, phosphorylated EGFR, MAPK, and phosphorylated MAPK were evidently expressed in 100, 54, 100, and 69% of the serous cystic neoplasms, and in 12%, none, 33, and 27% of the mucinous cystic neoplasms, respectively; the expression was significantly higher and more prevalent in the serous cystic neoplasms than in the mucinous cystic neoplasms. The expression of AKT and phosphorylated AKT was low in both the types of neoplasms. On average, EGFR transcripts in the serous cystic neoplasms and the mucinous cystic neoplasms increased 53.5- and 2.5-fold, respectively, as compared with that in normal tissues, with the increase in the former being significantly greater than that in the latter. Amplification of the EGFR gene was not detected in any of the examined serous cystic neoplasms. None of the tumors had mutations in any of the examined portions of the genes, except two mucinous cystic neoplasms with mutations in codon-12 of KRAS. These results indicate that EGFR and MAPK are actively involved in the pathobiology of serous cystic neoplasms and may therefore be potential diagnostic markers and therapeutic targets in patients with the above mentioned types of neoplasms.