We aimed to identify the factors for very early recurrence (within 6 months) of ampullary cancer following curative resection and to compare the immunohistochemical expression rate of various antibodies between the 2 main histologic subtypes of ampullary adenocarcinoma.In this retrospective study, the postoperative outcomes and clinicopathologic factors for very early recurrence that occurred in 14 of 93 patients who underwent pancreaticoduodenectomy (PD) for ampullary adenocarcinoma between January 2002 and August 2014 were analyzed. Thereafter, we identified the factors associated with very early recurrence following surgery. Additionally, we compared the expression rates of CK7, CK20, MUC1, MUC2, MUC5AC, MUC6, S100P, and CDX2 between the 2 main histologic subtypes of ampullary adenocarcinoma (NCC2019-0138).The patients who underwent PD for ampullary cancer were divided into 2 groups: very early recurrence and others. Compared with the other patients, the 14 patients (32.6%) who developed very early recurrence had shorter median disease-free survival (4.2 vs 49.7 months, P = .001) and overall survival (18.2 vs 113.7 months, P < .001). Large tumor, lymph node metastasis, and pancreatobiliary type were independently associated with very early recurrence of ampullary cancer following PD.Large tumor, lymph node metastasis, and pancreatobiliary type were the independent risk factors for very early recurrence of ampullary cancer following curative resection. Therefore, ampullary cancer patients with these factors should be considered to receive aggressive adjuvant treatment and frequent post-operative follow-up.