Objective: To correlate microscopic margin status with survival and local control in a large cohort of patients from a high-volume pancreatic cancer center. Design: Retrospective database review. A uniform procedure for margin analysis was used with 4-color inking (neck, portal vein groove, uncinate, and posterior pancreatic margin) by the surgeon in the operating room. Setting: A tertiary care hospital. Patients: We reviewed patients who underwent pancreaticoduodenectomy between September 1, 1997, and December 31, 2008, from a prospective, institutional database. Main Outcome Measures: Using Cox regression models, we identified pathologic characteristics associated with local recurrence (LR) after controlling for potential confounding variables. Overall and LR-free survival curves were generated by the Kaplan-Meier method. Results: Of 285 patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma, 97 (34.0%) had 1 or more positive microscopic margins (uncinate, 16.5%; portal vein groove, 8.8%; neck, 7.7%; and posterior, 10.5%). A total of 198 patients (69.5%) recurred, with the first site of failure being LR only in 47 (23.7%), local plus distant recurrence in 42 (21.2%), and distant recurrence only in 109 (55.1%). Patients with LR only were significantly more likely to have lymph node involvement (adjusted hazard ratio, 2.66; 95% CI, 1.25-5.63) or a positive posterior margin (adjusted hazard ratio, 4.27; 95% CI, 2.07-8.81). Patients with a positive posterior margin had significantly poorer LR-free survival with (P < .001) or without (P =.01) lymph node involvement. Conclusions: When systematically assessed, the incidence of positive microscopic margins is high. Positive posterior margins and lymph node involvement were each independently and significantly associated with LR.