(1) Aim: To evaluate clinicopathological features and postoperative outcomes including survival in patients who underwent pancreaticoduodenectomy (PD) for periampullary diseases. (2) Methods: We retrospectively reviewed 3078 cases of PD performed in our center for 25 years. Periampullary diseases were divided into benign and malignancy groups. All cases were also classified by location. The time of 25 years was divided to different periods (5 years per period) to compare outcomes. Overall survival was compared between subdivided periods. (3) Results: Hospitalization became significantly shorter from 28.0 days in the 1st period to 13.8 days in the 5th period. Overall complication rate was significantly increased since the 3rd period. The rate without postoperative pancreatic fistula (POPF) was high at 98.7% in the 1st period. This might be because drain amylase on the 3rd day after PD was not routinely checked in the past. Thus, POPF was not detected. In survival analysis of adenocarcinoma of pancreas, bile duct, and ampulla, overall survival was found to be improved significantly in recent years. (4) Conclusions: Our study revealed that outcomes were improved with increasing number of PDs performed. Although POPF and overall complications showed increases more recently, those were detected and managed, resulting in shorter hospitalization and improved outcomes.