For clarification of the pathogenetic role of viral infection in chronic glomerulonephritis, the renal effects of Coxsackie B4 virus (CB4) were examined in hyper-IgA (HIGA) mice. In experiment 1, HIGA mice (n = 75) were inoculated intravenously with live CB4 and inactivated CB4 once a month from 1 to 12 mo of age. In experiment 2, HIGA mice (n = 45) were inoculated intravenously with live CB4 and inactivated CB4 once at 6 wk of age. In experiment 3, 60 mice were inoculated intravenously with carbon and live or inactivated CB4 once at 6 wk of age. Mice in the control group were inoculated with vehicle. The kidneys were extirpated from five mice of each group killed with time after inoculation for histologic evaluation. The scores for mesangial IgA deposition, PCNA-positive cells, and matrix at 20 wk were higher in mice with live CB4 than in mice with inactivated CB4 or without CB4. On electron microscopic examination, swelling and detachment of endothelial cells from 24 h after inoculation and increase of serum IFN-gamma concentration were found in mice with live CB4. Many carbon particles were present in peripheral and central zones of the mesangium from 5 to 10 d in mice with carbon and live CB4. These results suggest that CB4 provokes exacerbation of renal pathologic findings in HIGA mice via endothelial injury, IFN-gamma production, and dysfunction of the mesangial pathway.