Helicobacter pylori causes chronic gastritis and is associated with an increased risk for the development of gastroduodenal ulcers, gastric cancer, and lymphoma.1 The diagnosis of active H pylori infection may be established with high confidence by using stool antigen assays, urease breath tests, and the Campylobacter -like organism (CLO) tests when used in previously untreated patients.2–9 Unfortunately, these methods do not permit mucosal assessment for inflammation-induced injury (or for the presence of other conditions) and are not sufficiently reliable when monitoring patients who receive eradication therapy or proton pump inhibitors.5,6,10–14 Thus, pathologic evaluation of mucosal biopsy specimens is widely used to document H pylori infection.15,16 Organisms are usually detectable in H&E-stained sections, but histochemical (eg, Giemsa, thiazine [modified Giemsa stain], alcian yellow, Genta, and Warthin-Starry) and immunohistochemical stains are widely used to enhance detection. Most authors have found ancillary stains to show comparably high sensitivities (>90%) for H pylori detection, so pathologists generally choose one or more of them based on personal preference.17–19 Rarely, if ever, do pathologists detect H pylori in “normal” uninflamed gastric tissue, and the added value of ancillary tests over H&E stains when histologic findings do not suggest infection has never been convincingly demonstrated. Therefore, the question of whether ancillary stains should be routinely used regardless of the histologic appearance of a gastric biopsy specimen on H&E remains a subject of considerable debate. Data-driven guidelines regarding the use of ancillary stains to detect H pylori in gastric biopsy specimens are not established. Pathologists have historically used their own discretion when ordering histochemical and/or immunohistochemical stains; however, many groups increasingly perform such studies on all gastric biopsy specimens (up-front) or on an established subset of cases, such as those accompanied …