Reovirus infection results in the stimulation of both humoral and cellular immune responses. Experiments conducted on mice indicate that cytotoxic T lymphocytes are evident within the first week of of infection. These T cells endure for months. The cytotoxic lymphocytes recognize many reovirus proteins, not just one. Additionally, the dominant T cell response is not directed only at one serotype of reovirus, but rather at protein epitopes which are common to all reoviruses. The complete role of the immune response in reovirus infection is not yet fully understood. However, prelimary research has shown that this T cell response does play a crucial role in suppression reoviral infection. It has also been postulated that the host's level of immune competence plays a part in determining susceptibility. Experiments have shown that both CD4+ and CD8+ cells are involved in the immune response.

It is now believed that reovirus infection causes the upregulation of class I and class II MHC expression. However, it is unclear what this upregulation actually does in terms of an immune response.

Antibody protection recognizes proteins in both capsids, further supporting the assertion that the immune system recognizes multiple viral epitopes. Cytokines also take part in the immune response, and reoviruses might also give rise to interferon production. The amount of interferon that is produced correlates with the amount of virus that infected cells give rise to. It is also possible for reovirus infection to result in immunosuppression in the patient.

A patient who endures rotavirus infection is likely to develop some immunity and subsequent infections will be less severe. Maternal IgG antibodies can be transmitted across the placenta, but these do not confer protection to the fetus or the neonate. However, IgA antibodies that are transferred from mother to baby in the colostrum do confer protection, making breast feeding an excellent choice for mothers, especially in the developing world where rotavirus infection is a major killer of infant children. This transfer of antibodies is most effective during the first few days of the baby's life.