We hypothesized that consumption of the (n-3) PUFA, docosahexaenoic acid (DHA), modulates the mucosal immune response to enteric infection with respiratory enteric orphan virus (reovirus), a model intestinal pathogen. Mice were fed either AIN-93G control diet, containing 10 g/kg corn oil and 60 g/kg high oleic acid safflower oil, or AIN-93G, containing 10 g/kg corn oil and 60 g/kg DHA-enriched fish oil, for 4 wk and then orally gavaged with reovirus strain Type 1 Lang, (T1/L). Reovirus-specific IgA antibody was first detectable in the feces of mice fed a control diet at 6 d postinfection (PI) and was further elevated at 8 and 10 d PI. IgA responses in DHA-fed mice were similar at 6 and 8 d PI but greater at 10 d PI (P < 0.05). Both reovirus-specific serum IgA and IgG(2a) were comparably induced in mice fed control or DHA diets. Reovirus-specific IgA and IgG(2a) secretion by ex vivo Peyer's patch, lamina propria, and spleen cultures derived from control and DHA groups were comparable. Although both groups carried similar numbers of reovirus plaque forming units per intestine, DHA-fed mice shed nearly 10 times more viral RNA in feces than control mice at 2, 4, and 6 d PI (P < 0.05). However, viral RNA was not detectable in either group at 8 and 10 d. Taken together, these data suggest that DHA consumption did not markedly alter mucosal or systemic Ig responses to reovirus but delayed clearance of the virus from the intestinal tract.