Background: An EUS-guided FNA (EUS-FNA) and a therapeutic ERCP are frequently required for the evaluation of patients who were seen for an obstructing periampullary lesion. Objective: To determine the feasibility and outcomes of combining an EUS-FNA and a therapeutic ERCP into a single session. Design: Retrospective single-center study. Setting: Tertiary-referral cancer center. Patients: A total of 114 patients with a suspected malignant obstructing lesion in the pancreatic head. Interventions: An EUS with or without FNA plus an ERCP. Main Outcome Measurements: Duration, diagnostic yield, and complication rate of the combined procedures. Results: The mean (SD) total procedure time (EUS, with or without FNA plus ERCP) was 73.6 ± 30 minutes, with a median of 66 minutes (range 25-148 minutes). In many cases, cytologic diagnosis from FNA became available during an ERCP, which obviated the need for further sampling. EUS-FNA had a sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of 84.6%, 100%, 100%, 62.9%, and 87.8%, respectively. During an ERCP, endoscopic sphincterotomies were performed in 51 patients, and biliary stents were placed in 96 patients. Twelve patients (10.5%) had a complication, with 6 having postprocedural pancreatitis. Limitations: Retrospective single-center experience. Conclusions: Combined EUS-FNA and therapeutic ERCP is technically feasible, with a complication rate no higher than the component procedures, while efficiently providing tissue diagnosis and biliary drainage.