Rotavirus infection was studied in adult nude mice (BALB/c background), alpha beta or gamma delta and alpha beta/gamma delta T cell receptor (TCR) knockout (-/-) mice (C57BL/6 and C57BL/6 x 129 backgrounds), and SCID mice (C57BL/6 background). The gamma delta TCR -/- mice cleared infection just like control mice. All of the nude mice, alpha beta, and alpha beta/gamma delta TCR -/- mice cleared primary rotavirus infection, with a short delay, compared to immunocompetent control mice and developed a rotavirus-specific intestinal IgA measured by ELISA. Elispot analysis with spleen and lamina propia cells showed that the virus-specific intestinal IgA response in immunocompetent C57BL/6 mice was similar to the gamma delta TCR -/- mice and 7- to 60-fold higher than in the alpha beta TCR -/- and alpha beta/gamma delta TCR -/- mice. Likewise, the response of nude +/- mice was 20 times greater than that of nude -/- littermates. While the intestinal IgA antibodies of C57BL/6 mice, gamma delta TCR -/- mice, and nude +/- mice recognized insect cells infected with recombinant baculovirus expressing rotavirus VP6 and VP4 proteins, those of the alpha beta TCR -/-, alpha beta/gamma delta TCR -/-, and nude -/- mice recognized only VP6. Immunocompetent C57BL/6 mice depleted of CD4+ T cell developed similar levels of rotavirus-specific intestinal IgA as the alpha beta TCR -/- mice, suggesting that this T cell-independent IgA response is present in normal mice. In contrast to previously published results with BALB/c SCID and RAG 2 -/- (C57BL/6 x 129 background) mice, all of which become chronically infected with murine rotavirus, 40% of the C57BL/6 SCID mice cleared primary rotavirus infection. These results suggest that both a T cell-independent antibody response and innate mechanisms can contribute to immunity to murine rotavirus and show that gamma delta T cells are not necessary for efficient clearance of primary rotavirus infection in mice.