OBJECTIVES: Malignant 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. METHODS: Twenty 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. RESULTS: Twenty 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%, CONCLUSIONS: In 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.