Both human and H. pylori populations are polymorphic for the expression of Lewis antigens. Using an experimental H. pylori challenge of rhesus monkeys of differing Lewis phenotypes, we aimed to determine whether H. pylori populations adapt their Lewis phenotypes to those of their hosts. After inoculation of four monkeys with a mixture of seven strains identified by RAPD-polymerase chain reaction, H. pylori Lewis expression was followed in 86 isolates obtained over 40 wk. Host Lewis^a/b secretion status was characterized by immunological assays. Fingerprints of the predominating strain (J166) were identical in all four animals after 40 wk, but its Lewis phenotype had substantial variability in individual hosts. At 40 wk, J166 populations from two Lewis^a-b+ animals predominantly expressed Lewis^y. In contrast, J166 populations had switched to a Lewis^x dominant phenotype in the two Lewis^a+b- animals; a frame shift in futC, regulating conversion of Lewis^x to Lewis^y, accounted for the phenotypic switch. The results indicate that individual cells in H. pylori populations can change Lewis phenotypes during long-term colonization of natural hosts to resemble those of their hosts, providing evidence for host selection for bacterial phenotypes.--Wirth, H.-P., Yang, M., Sanabria-Valentín, E., Berg, D. E., Dubois, A., and Blaser, M. J. Host Lewis phenotype-dependent Helicobacter pylori Lewis antigen expression in rhesus monkeys.