Background: Ampulla of Vater cancer (AoV Ca) is a rare tumor, and its adjuvant treatment has not been established. The purpose of this study was to find out prognostic factors including host immunity and role of adjuvant treatment in AoV Ca. Methods and Findings: We reviewed 227 AoV Ca patients with curative resection. Clinical characteristics, adjuvant treatment, disease-free survival (DFS) and overall survival (OS) were analyzed. Among all patients, 63.9,36.1 and 33.9% had T1/T2, T3/T4 stage and lymph node-positive disease (LN+), respectively. OS of all patients was 90.9 months (95% CI: 52.9-129.0). OS was different according to neutrophil-to-lymphocyte ratio (HR 1.651, 95% CI: 1.11-2.47), platelet-to-lymphocyte ratio (HR 1.488,95% CI: 1.00-2.21) and systemic inflammatory index (HR 1.669, 95% CI: 1.13-2.47). In multivariate analysis, adverse prognostic factors for OS included vascular invasion (HR 2.571, 95% CI: 1.20-5.53) and elevated CA 19-9 (HR 1.794, 95% CI: 1.07-3.05). A total of 104 patients (46.3%) received adjuvant treatment (25 out of 111 of T1/T2 & LN (-), 79 out of 116 of T3/T4 or LN (+)). In T3/T4 or LN (+) stage, adjuvant CCRT with maintenance chemotherapy provided the longest OS (5-year OS rate: 47.0 vs. 41.4%). Conclusions: Vascular invasion and elevated CA 19-9 were adverse prognostic factors in resected AoV Ca. In T3/T4 or LN (+) stage, adjuvant CCRT with maintenance chemotherapy provided the best survival outcome. Adjuvant treatment should be further defined in AoV Ca, especially with poor prognostic factors.