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Background: The quality of histopathology slides of endoscopic biopsies from different laboratories varies, but the effect of biopsy quality on outcome is unknown. Hypothesis: The ability to demonstrate a histologic lesion in the stomach or duodenum of a dog or cat is affected by the quality of endoscopic biopsy samples submitted. More endoscopic samples are needed to find a lesion in poor-quality tissue specimens. Animals: Tissues from 99 dogs and 51 cats were examined as clinical cases at 8 veterinary institutions or practices in 5 countries. Methods: Histopathology slides from sequential cases that underwent endoscopic biopsy were submitted by participating institutions. Quality of the histologic section of tissue (inadequate, marginal, adequate), type of lesion (lymphangiectasia, crypt lesion, villus blunting, cellular infiltrate), and severity of lesion (normal, mild, moderate, severe) were determined. Sensitivity of different quality tissue samples for finding different lesions was determined. Results: Fewer samples were required from dogs for diagnosis as the quality of the sample improved from inadequate to marginal to adequate. Duodenal lesions in cats displayed the same trend except for moderate duodenal infiltrates for which quality of tissue sample made no difference. Gastric lesions in dogs and mild gastric lesions in cats had the same trend, whereas the number of tissue samples needed to diagnose moderately severe gastric lesions in cats was not affected by the quality of tissue sample. Conclusions and Clinical Importance: The quality of endoscopically obtained tissue samples has a profound effect on their sensitivity for identifying certain lesions, and there are differences between biopsies of canine and feline tissues.