Ampullary adenocarcinoma (AmpCA) carries a better overall survival (OS) rate than other periampullary cancers. We examined clinicopathologic features in AmpCA for impact on OS. Records of patients undergoing pancreaticoduodenectomy from 2000 to 2007 for AmpCA were reviewed and histological specimens were reanalyzed. Of 302 patients undergoing pancreaticoduodenectomy for malignancy, 45 (14.9%) had AmpCA. Mean age was 61.3 +/- 12.2 years, mean tumor size was 2.6 +/- 1.3 cm, 57 per cent were > or = T3 tumors, 42 per cent were N1 stage, 13 (49%) had perineural invasion (PNI), and 29 (64%) had lymphovascular invasion (LVI). Thirteen were intestinal (29%), 14 were pancreaticobiliary (31%), and 18 were mixed (40%). Median OS was 42 months (range 4-80 mos). On log rank testing, > or = T3 (24 vs 65 mos, P < 0.01), N1 (25 vs 61 mos, P < 0.01), poor differentiation (24 vs 44 mos, P = 0.01), pancreaticobiliary subtype (23 vs 44 mos, P = 0.01), and PNI (23 vs 44 mos, P < 0.01) were significant for worse survival. By multivariate analysis, N1 disease (hazard ratio [HR] 4.50, 95% confidence interval [CI] 1.16-17.40) and PNI (HR 4.62, CI 1.11-19.21) maintained associations with worse survival, whereas histological subtype did not. N1 disease and presence of PNI demonstrated independent associations with worse survival. Given high percentage of mixed histology, PNI may be more informative than the subtype in predicting outcome for patients with AmpCA.