ObjectivesMalignant double obstruction, defined as the simultaneous presence of biliary and gastric outlet obstruction, represents a challenging clinical scenario. Previous retrospective experiences have demonstrated shorter dysfunction‐free survival (DyFS) of endoscopic ultrasound‐guided choledochoduodenostomy (EUS‐CDS) versus EUS‐hepaticogastrostomy (EUS‐HGS) in this setting, but no prospective evidence is available.MethodsTwenty consecutive patients with malignant double obstruction, treated with EUS‐gastroenterostomy (and EUS‐guided biliary drainage, following a previously failed ERCP, were enrolled in a prospective observational study (ClinicalTrials.gov NCT04813055) comparing EUS‐CDS versus EUS‐HGS. Efficacy and safety were evaluated, with Biliary Dysfunctions as the primary outcome and DyFS using Kaplan‐Meier estimates as a primary measure.ResultsTwenty patients (75% with pancreatic cancer, 50% with metastatic disease) with EUS‐gastroenterostomy were included (seven EUS‐CDS and 13 EUS‐HGS). No significant difference was detected at baseline. Technical success was 100% in both groups. EUS‐CDS compared to EUS‐HGS showed similar clinical success (100% vs. 92.3%, p = 0.5), a higher rate of post‐procedural adverse events (42.9% vs. 7.7%, p = 0.067, mostly related to severe/fatal cholangitis in the EUS‐CDS group) and a higher rate of biliary dysfunctions during follow‐up (71.4% vs. 16.7%, p = 0.002).DyFS was significantly shorter in the EUS‐CDS group (39 [15–62] vs. 268 [192–344] days, p = 0.0023), with a 30‐days DyFS probability of 57.1% vs. 100% (hazard ratio = 7.8 [1.4–44.2]).ConclusionsIn this prospective comparison of patients with malignant double obstruction undergoing EUS‐gastroenterostomy, treating jaundice with EUS‐CDS versus EUS‐HGS resulted in a reduced probability of survival without biliary events and an increased risk of biliary dysfunctions (number needed to harm = 1.8), with detection of severe/fatal cholangitis.