Critical factors that are important in protection from rotavirus infection have remained elusive. We demonstrate here that inbred mice (C57BL/6 and BALB/c) exhibit differences in: (1) susceptibility to and (2) VLP-induced protection from rotavirus infection. Comparing protection induced by 2/4/6/7-VLPs with inactivated and live rotavirus, intranasally induced protection was dependent on dsRNA or minor structural proteins and correlated with intestinal antibody, while orally induced protection required immunization with replicating virus. Combination oral/intranasal vaccination did not improve VLP protective efficacy. These studies indicate that host, viral, and vaccine factors determine the level of protective efficacy induced by VLPs.