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Objective: To investigate biological differences and prognostic indicators of different ampullary cancer (AC) subtypes.Summary Background Data:AC is associated with a favorable prognosis compared to other periampullary carcinomas. Aside from other prognostic factors, the histological origin of AC may determine survival. Specifically, the pancreatobiliary subtype of AC displays worse prognosis compared to the intestinal subtype. However, knowledge of inherent molecular characteristics of different periampullary tumors and their effects on prognosis has been limited. Methods:Gene expression profiling was used in order to screen for differential gene expression between six PDAC cases and 12 AC cases. Among others, hepatocyte nuclear factor 4α (HNF4α) mRNA over-expression was observed in AC cases. Nuclear HNF4α protein expression was assessed using tissue microarrays consisting of 99 individual AC samples. Correlation of HNF4α expression with clinicopathological data and survival was calculated. Results: HNF4α mRNA is 7.61 fold up-regulated in AC compared to that in PDAC. Bioinformatics analyses indicated its key role in dysregulated signaling pathways. Nuclear HNF4α expression correlates with histological subtype, grading, CDX2 positivity, MUC1 negativity and presence of adenomatous components in the carcinoma. The presence of HNF4α is a univariate predictor of survival in AC mean survival 50 vs. 119 months, P=.002). Multivariate analysis revealed that HNF4α negativity (HR=17.95, 95% CI: 2.35-136.93, P=.005) and lymph node positivity (HR=3.33, 95% CI 1,36-8.18, P=.009) are independent negative predictors of survival. Conclusions:Immunohistochemical determination of HNF4α expression is an effective tool for distinguishing different AC subtypes. Likewise, HNF4α protein expression is an independent predictor of favorable prognosis in carcinoma of the papilla of Vater.