The information on the clinicopathologic/outcome differences between ampullary adenocarcinoma (AC) and pancreatic adenocarcinoma (PC) has been conflicting to the extent that it still is questioned whether ACs need to be recognized separately from PCs. The characteristics of 413 ACs were compared with those of 547 PCs. The ACs had a better prognosis than the PCs (5-year survival, 57 % vs 23 %; p < 0.001). Even the pancreatobiliary (PB)-type ACs had a better prognosis (5-year survival, 46 % vs 23 %; p < 0.001). Several differences also were identified as contributing factors: (1) the preinvasive adenomatous component often constituted a significant proportion of the mass in ACs (>50 % of the tumor in 16 % vs 1.5 %; p < 0.001); (2) the mean size of the carcinoma was smaller in ACs (2.5 vs 3.2 cm; p < 0.001): when matched for invasion size, the survival advantage of AC was minimized, and when matched for invasion size larger than 2 cm, the survival advantage of AC lost its statistical significance; (3) lymph node (LN) metastases were less common in ACs (49 % vs 71 %; p < 0.001); (4) the definitive R1 rate was lower in ACs (4 % vs 23.5 %; p < 0.001); and (5) non-PB and non-tubular adenocarcinoma types were more common in ACs (17 % vs 3 %; p < 0.001). Comparatively, ACs have better clinical survival than PCs. Potential contributing factors are the relative abundance of the preinvasive component, smaller invasion, lower LN metastasis rate, higher resectability, and common occurrence of less aggressive histologic phenotypes (intestinal, medullary, mucinous). However, this survival advantage is sustained even in PB-type ACs, highlighting the importance of accurately determining the site of origin.