Perioperative hemodynamic optimization therapy is used to improve cardiac function to meet the increased demand during the perioperative period and to reduce hypervolemia or hypovolemia, tissue hypoperfusion and other postoperative complications. The present single center retrospective study aimed to compare perioperative hemodynamic optimization therapy and usual protocols in terms of perioperative cardiac function in 252 patients who underwent elective pancreaticoduodenectomy. Patients underwent elective pancreaticoduodenectomy under usual protocols of enhanced recovery after surgery procedures without intraoperative fluid optimization (UC; n=142) or with intraoperative fluid optimization (FO; n=110). For intraoperative fluid and vasoactive medication optimization, the patients of the UG cohort underwent usual cardiovascular monitoring and in the FO cohort, fluid interventions were given if stroke volume variations were >20% during and at the end of surgeries. The length of the hospital stay (discharge from operation theater to discharge from the ward) of the FO cohort was shorter than that of the UC cohort (11.02±2.07 days vs. 14.95±3.97 days; P<0.0001). The fluid balance (total input fluid-total output fluid) was higher in the UC cohort than that in the FO cohort (6,101±695 ml vs. 4,623±358 ml; P<0.0001). The number of patients that required intraoperatively metaraminol was greater in the UC cohort than in the FO cohort (P<0.0001). The number of patients that required intraoperatively noradrenaline (P<0.0001) and dopamine/dobutamine (P<0.0001) administration was greater in the FO cohort than those in the UC cohort. A greater number of patients in the UC cohort suffered from pancreatic fistula, arrhythmia, postoperative delirium, electrolyte disturbances, hyponatremia, refractory analgesia and required intraoperative blood products (P<0.05 vs. FO cohort). Pancreaticoduodenectomy under usual protocol with intraoperative fluid optimization may have perioperative and postoperative benefits (level of evidence, 3; technical efficacy stage, 1).