Background The premise that allogeneic red blood cell transfusion (RBCT) contributes to adverse oncologic outcomes after surgery remains controversial. We examined the effects of RBCT during and after pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) on disease recurrence and survival. Methods A prospective database of 220 patients undergoing PD for PDAC from 2000 to 2008 was reviewed and transfusion data collected. Univariate and multivariate analyses were performed for factors influencing RBCT, recurrence-free survival (RFS), and overall survival (OS). The effect of amount and timing (intraoperative vs. postoperative) of RBCT was analyzed. Results One hundred forty-seven patients (67%) received RBCT: 70 (32%) received 1 to 2 units, and 77 (35%) received >2 units. Median RFS and OS for the entire cohort was 12 and 16 months, respectively. RBCT of >2 units was associated with reduced RFS (9 vs. 15 months; P  = 0.033) and OS (14 vs. 20 months; P  = 0.003). Stratified by timing of transfusion, postoperative RBCT was associated with shortened RFS and OS. Controlling for age, body mass index, comorbidities, tumor factors, and major complications, each incremental unit of postoperative RBCT was associated with reduced RFS (hazard ratio 1.10, 95% confidence interval 1.02–1.18) and OS (hazard ratio 1.08, 95% confidence interval 1.03–1.12). Low hemoglobin and presence of comorbidities were the only preoperative factors independently associated with RBCT. Conclusions Allogeneic red blood cell transfusion after PD for PDAC is independently associated with earlier cancer recurrence and reduced survival, in particular when administered postoperatively and in larger quantities. Blood-conservation methods are especially indicated for patients with preoperative anemia and medical comorbidities.