The severity of infections caused by the malaria parasite Plasmodium is in part due to the rapid multiplication cycles in the blood of an infected individual. A fundamental step in this phenomenon is the invasion of selected erythrocytes of the host by the parasite. The py235 rhoptry protein multigene family of the rodent malaria parasite Plasmodium yoelii has been implicated in mediating host cell selection during erythrocyte invasion and virulence. Here we show using quantitative real-time polymerase chain reaction and Western blot analysis that variations in the amounts of py235 may be a mechanism that the parasite uses to define its host cell repertoire. High levels of py235 expression leads to a wider range of erythrocytes invaded and therefore increased virulence. In contrast, to evade PY235-specific immunity, the parasite downregulates py235 thereby decreasing the host cell repertoire and virulence. These results demonstrate a new mechanism where variations in the amounts of parasite ligand define the parasite host cell repertoire and enable it to evade host immunity.