Monoclonal antibodies were used in an enzyme-linked immunosorbent assay for the detection of human Lewis immunodeterminants in the lipopolysaccharide of Helicobacter pylori. In 94 H. pylori isolates, expression of Lewis(x) (Le(x)) and Le(y) was a stable phenotypic marker independent of the growth medium and cell age; 46 (49%) of the isolates expressed both and 34 (36%) of the isolates expressed either Le(x) or Le(y); 14 (15%) were negative for both determinants. Twelve (13%) isolates expressed Le(b), 3 (3%) expressed Le(a), and 2 (2%) expressed sialyl-Le(x). H. pylori isolates positive for both Le(x) and Le(y) were predominantly cagA+ (P < 0.001) and possessed the s1 signal sequence (P < 0.05) and the m1 midregion type (P = 0.033) of vacA. Isogenic mutants of H. pylori CPY3401 were created by interruption of the cagA, picB, or ureA gene. The cagA-ablated strain (but not the picB- and ureA-ablated mutant strains) had significantly (P < 0.01) diminished expression of Le(y) compared with that of the wild-type strain; for all four strains, expression of Le(x) was similar. In conclusion, 89% of H. pylori isolates express Le determinants in their lipopolysaccharide, mimicking human cell surface glycoconjugates. Strong expression of Le(x) and Le(y) by cagA+ isolates could counterbalance their enhanced proinflammatory activities and thereby facilitate persistence.