Helicobacter pylori seems universally distributed in all human populations, with high prevalence in the third world. Because H. pylori is an ancestral indigenous microbe of the human stomach, we hypothesized that its prevalence in isolated Amerindians would be high. A serologic study was performed on 19 Guahibo-Piaroa and 17 Warao in Venezuela, using H. pylori whole cell (WC) and CagA antigens from US strains. For Guahibo-Piaroa Amerindians, CagA seropositivity was 95%, but WC seropositivity was only 74%. For Warao, both CagA and WC seropositive proportions were low (65% and 76%, respectively). Because all CagA-seropositive individuals carry H. pylori, the results suggest that there has been bacterial antigen divergence, probably caused by genetic drift/natural selection, on humans and their microbes in isolated human groups.