The effect of dietary exposure to vomitoxin on serum immunoglobulin A (IgA) was evaluated in the B6C3F1 mouse. Levels of serum IgA were elevated maximally in mice fed 25 ppm vomitoxin in comparison with levels in mice fed 2, 10 or 50 ppm vomitoxin. Significant increases were detectable after as few as 4 wk in mice fed 25 ppm vomitoxin, and IgA levels were increased more than 17-fold after 24 wk of toxin exposure. Serum IgA also exhibited a marked shift from primarily monomeric IgA to primarily polymeric IgA during vomitoxin treatment. Serum IgG and IgM decreased in treated mice, suggesting that the effect was isotype-specific. Elevated serum IgA was not observed in mice when control diet was fed at levels equivalent to those consumed by vomitoxin-treated mice, which exhibited feed refusal. IgA production was significantly increased in both spontaneous and mitogen-stimulated splenocyte cultures from mice exposed to vomitoxin in comparison with cultures prepared from ad lib. or feed-restricted controls. Immunofluorescence staining revealed marked accumulation of mesangial IgA and electron microscopy showed electron-dense deposits in the glomeruli of vomitoxin-treated mice but not in those of controls. Dysregulation of IgA production and accumulation of glomerular IgA as observed in this study were highly analogous to the characteristics of human IgA nephropathy, the most common form of glomerulonephritis worldwide.