Background: Data on sensitivities of biopsy tests for Helicobacter pylori diagnosis after modern eradication therapy are limited. We assessed diagnostic yield of endoscopic biopsy tests before and after therapy in 2 U.S, multicenter double-blind trials of 10-day proton pump inhibitor-based triple therapy versus dual antibiotic therapy. Methods: Three hundred one patients with duodenal ulcer and ii pylori infection had endoscopy at baseline and at 8 weeks. Four antral and 3 body biopsies were taken at both endoscopies: 1 antral biopsy for a rapid urease test (CLOtest), 2 antral and 2 body biopsies for histologic examination (Genta stain), and 1 antral and 1 body biopsy for culture. Results: The 2 same-site biopsies (antral or body) for histologic examination were in agreement in 97% of cases before treatment and 100% after triple therapy. Histologic examination of antral biopsies without body biopsies missed H pylori infection in 2% of patients before treatment and 5% after triple therapy Posttreatment sensitivities for triple therapy were significantly lower than pretreatment sensitivities for all tests (e.g., 18% decrease in sensitivity in antral histology, 22% decrease in antral culture); decreases in sensitivity were greater after triple therapy than after the less effective dual therapy, CLOtest plus histology had a post-treatment sensitivity of 96% in the triple therapy group. Conclusions: A single antral biopsy for histology provides excellent sensitivity for H pylori in untreated patients, but, after effective therapy, sensitivities of biopsy tests decrease. Use of more than one method of testing may increase diagnostic yield when assessing post-treatment H pylori status with endoscopy, whereas the addition of multiple biopsies for each type of test is of more limited value.