To determine the clinical significance of Helicobacter pylori seropositivity and seronegativity in healthy blood donors, we carried out a serological evaluation of Helicobacter pylori status and endoscopy in a healthy blood donors population. In all, 1010 donors were screened for Helicobacter pylori by IgG ELISA and assessed for pepsinogen I and gastrin levels by RIA; 298 IgG seropositive and 61 seronegative subjects underwent endoscopy with biopsies. Of 359, 165 were also tested for CagA by western blotting. Of the 298 IgG seropositives, 274 were shown to be infected on biopsy testing. Endoscopy revealed 70 peptic ulcers, 41 cases of erosive duodenitis, and two gastric cancers. In all 105 seropositive donors were tested for CagA and 69 were CagA positive [34/58 gastritis (58.6%), 24/35 duodenal ulcer (68.6%) and 11/12 gastric ulcer (91.6%)]. Histologically active/chronic gastritis was associated with CagA: 88.4% vs 50% (CagA seropositive vs seronegative). Of the 61 IgG seronegatives, 59 were negative on biopsy testing. At endoscopy three had duodenitis. Of the 60/61 IgG seronegatives tested for CagA, one had a moderate reaction. Duodenal ulcer donors showed higher pepsinogen I levels than donors without duodenal ulcers (97.7 μg/ml vs 80.9 μg/ml respectively). Screening for Helicobacter pylori and anti-CagA seropositivity and pepsinogen I can identify individuals likely to have gastroduodenal pathology even in the absence of symptoms.