Background: Despite advances in preoperative imaging and Histopathological techniques, the ability to accurately diagnose periampullary malignancy prior to PD remains a challenge. This paper examines the outcomes ability to accurately define malignancy in patients undergoing PD at a non university tertiary care center (NUTCC)Methods: Medical records of 122 patients, who underwent PD by a single surgeon between September 2005 to August 2008 at a high volume NUTCC, were analyzed. An attempt to establish preoperative diagnosis with endoscopy and or endoscopic ultrasound was made in all patients with a final malignant diagnosis. The patients were managed by a multidisciplinary team consisting of a gastroenterologist, surgeon, hepatobiliary fellow, general surgery residents, ICU nursing staff, operating room team, and a surgery floor nursing staff. The records were reviewed with respect to preoperative and postoperative data, thirty-day mortality, morbidity and histopathology data.Results:Of the total 120 patients who underwent PD for resection of periampullary masses. 63% patients were found to have a diagnosis of periampullary carcinoma on final histopathology. Of these, 9% (7 patients) had a negative preoperative diagnosis for malignancy. All seven of these patients had significant comorbidities with 5 patients (70%) and 2 patients (30%) with ASA Class III and ASA class IV respectively. All seven of these patients were taken for PD based on the clinical suspicion. . Diagnosis of periampullary malignancy was confirmed intraoperatively,and on subsequent final histopathology. There was no mortality in any of the patients. Significant morbidity was seen in 2 patients. On final histopathology, all patients had negative margins, and 2 patients were node positive. 6 patients with suspicious preoperative histopathology, who had no evidence of malignancy on final histopathology, underwent PD. There was no mortality in any of these patients. Only one patient had significant comorbidity in the post operative period. The positive predictive value of preoperative histopathology was 0.92 whereas the negative predictive value was 0.84.Conclusions: PD is justified even in the presence of a negative preoperative histopathology at a NUTCC with results that meet reported outcomes and benchmarks. The evaluation of patients with potential periampullary masses requires a dedicated multidisciplinary team and aggressive surgery.