BACKGROUND: The aim of this study was to evaluate the expression of epidermal growth factor receptor (EGFR) and insulinlike growth factor 1 receptor (IGF‐1R) proteins and IGF‐1R gene copy numbers in pancreatic ductal adenocarcinoma in relation to patients' characteristics and prognosis. METHODS: Immunohistochemical staining was performed on formalin‐fixed paraffin‐embedded tissue derived from tumor specimens recovered during surgery. Slides were evaluated for membranous EGFR and IGF‐1R staining using both the HercepTest and the semiquantitative H‐score systems. Chromogenic in situ hybridization was performed to quantify IGF‐1R gene copy number. The primary outcome was the association between EGFR expression, IGF‐1R expression—in both neoplastic epithelial and stromal cells—or IGF‐1R gene copy number and overall survival. Secondary outcomes included associations between EFGR and IGF‐1R expression and pathologic variables. RESULTS: A total of 105 patients were included. EGFR expression was present in 30.4% of cases and was associated with lymph node metastasis (P = .038). IGF‐1R was overexpressed in 53% of tumors and correlated with higher tumor grade (P = .033). High membranous expression of EGFR (P < .001) and/or IGF‐1R (P = .004), the cytoplasmic detection of EGFR (P = .027), and high expression levels of IGF‐1R in the tumoral stroma (P < .001) were all associated with shorter overall survival, being significantly better in patients who simultaneously do not express membranous EGFR or stromal IGF‐1R. CONCLUSIONS: EGFR and IGF‐1R expression, in neoplastic and stromal cells, seems to be an important prognostic factor. Cancer 2012;3484–3493. © 2011 American Cancer Society.