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Introduction Histological analysis of regular duodenal biopsies to study morphologic changes after duodenal ablation for type 2 diabetes (T2D) and metabolic syndrome is hampered by the variability in tissue orientation. We designed an optimized tissue acquisition protocol using duodenal cold snare resections to create tissue microarrays (TMAs) and to allow for single-cell RNA sequencing (scRNA-seq). Methods The open-label DIRECT study included patients undergoing an upper gastrointestinal interventional endoscopy for non-duodenal indications. All underwent 1-2 single-piece duodenal cold snare resections. Endpoints were safety, adequate histological orientation of specimen and TMA, and tissue dissociation quality for scRNA-seq. The optimized tissue acquisition protocol was validated in a duodenal ablation study, EMINENT-2. Results In DIRECT, nine patients were included in whom a total of 16 cold snare resections were obtained. No (severe) adverse events ([S]AEs) occurred. 80% of specimens and corresponding TMAs showed optimal tissue orientation. Further improvement was achieved by reducing tissue damage during endoscopic retrieval and improving histologic evaluation by eliminating ink use and pinning the tissue on cork. High-quality tissue dissociation scores for scRNA-seq were achieved in 13/18 (72%) samples. In EMINENT-2, 38 cold snares were obtained without (S)AEs, histopathologic analysis showed good orientation in all samples and dissociation scores for scRNA-seq were qualified in 35/38 (92%) samples. Discussion Duodenal cold snare resection is safe and can provide high-quality tissue for optimally oriented TMAs and high-quality tissue dissociation scores for scRNA-seq;Clinicaltrials.gov, NCT06333093, NCT05984238. This approach will allow mechanistic studies into the effects of duodenal ablation on metabolic syndrome and T2D.