We have recently shown that CD8+ T cells mediate clearance of rotavirus infection in mice. B-cell-deficient J(H)D knockout (-/-) mice depleted of CD8+ T cells become chronically infected with murine rotavirus, and beta2 microglobulin -/- and other mice depleted of CD8+ T cells have a 1- to 4-day delay in clearance of primary rotavirus infection. A role for CD8+ T cells in protection from reinfection with rotavirus was suggested by these studies, because J(H)D -/- mice rechallenged 6 to 8 weeks after primary infection shed smaller quantities of viral antigen and for fewer days than naive mice. Here we show that 8, 11, 13, and 18 days after primary infection the J(H)D -/- mice are almost completely resistant to reinfection and that they are still partially protected from reinfection 6 weeks, 5 months, and 8 months after primary infection. Protection against reinfection was dependent on CD8+ T cells, since J(H)D -/- mice depleted of CD8+ T cells by administration of an anti-CD8 monoclonal antibody became chronically infected with rotavirus upon rechallenge 13 days, 18 days, 6 weeks, and 5 months after primary infection. Thus, CD8+ T cells can actively mediate almost complete short-term and partial long-term protection from reinfection.