Background/Objective: The benefit of adjuvant therapy in ampullary cancer (AMPAC) patients following pancreatoduodenectomy (PD) is debated. The aim of this study was to determine the role of adjuvant therapy after pancreatoduodenectomy (PD) in histological subtypes of AMPAC. Methods: Patients undergoing PD for AMPAC at 5 high-volume European surgical centers from 1996 to 2017 were identified. Patient baseline characteristics, surgical and histopathological parameters, and long-term overall survival (OS) after resection were evaluated. Results: 214 patients undergoing PD for AMPAC were included. ASA score (ASA1-2 149 vs. ASA 3–4 82 months median OS, p = 0.002), preoperative serum CEA (CEA <0.5 ng/ml 128 vs. CEA >0.5 ng/ml 62 months, p = 0.013), preoperative serum CA19-9 (CA19-9 < 40 IU/ml 147 vs. CA19-9 > 40IU/ml 111 months, p = 0.042), T stage (T1-2 163 vs. T3-4 98 months, p < 0.001), N stage (N0 159 vs. N+ 110 months, p < 0.001), grading (G1-2 145 vs. G3-4 113 months, p = 0.026), R status (R0 136 vs. R+ 38 months, p = 0.031), and histological subtype (intestinal subtype 156 vs. PB/M subtype 118 months, p = 0.003) qualified as prognostic parameters. In multivariable analysis, ASA score (HR 1.784, 95%CI 0.997–3.193, p = 0.050) and N stage (HR 1.831, 95%CI 0.904–3.707, p = 0.033) remained independent prognostic factors. In PB/M subtype AMPAC, patients undergoing adjuvant therapy showed an improved median overall survival (adjuvant therapy 85 months vs. no adjuvant therapy 65 months, p = 0.005), and adjuvant therapy remained an independent prognostic parameter in multivariate analysis (HR 0.351, 95%CI 0.151–0.851, p = 0.015). There was no significant benefit of adjuvant therapy in intestinal subtype AMPAC patients. Conclusion: Adjuvant treatment seems indicated in pancreatobiliary or mixed type AMPAC.