Immune evasion is frequently cited as the main reason for antigenic variation in pathogenic microorganisms. To better understand the role of switching of variant-specific surface proteins (VSPs) in Giardia lamblia-host interactions, antigenic variation during infections of mice and gerbils was examined, using clones that predominantly expressed unique VSPs. As expected, VSPs were selected against during infections of immunocompetent hosts. In contrast, in immunodeficient hosts, some VSPs were selected for and others were selected against. These diverse patterns of selection demonstrate that there are host-VSP interactions that exert both positive and negative selective pressures on parasites, independent of the adaptive immune response. Furthermore, selection was dependent on both the particular VSP and the host. Thus, the large number of VSP genes in G. lamblia may allow the parasite to infect multiple different hosts, and antigenic variation could be a mechanism to expand the parasite's host range.