Rhesus rotavirus (RRV)-inoculated neonatal BALB/c mice develop an immune-mediated inflammation of extra- and intrahepatic bile ducts that progresses to biliary obstruction and death by 3 wk of age. Livers of diseased animals demonstrate increased numbers of T lymphocytes with elevated expression of helper T cell type 1 (Th1) cytokines at 1 wk, which transitions to increased numbers of macrophages and high expression of the proinflammatory cytokine tumor necrosis factor (TNF)-α by 2 wk. We employed both pharmacologic and genetic approaches for attenuation of TNF-α to determine whether it plays a causal role in injury. First, RRV-inoculated BALB/c mice were subjected to multiple treatments with either the TNF receptor I (TNF-RI)–Fc fusion protein etanercept or neutralizing antibodies to mouse TNF-α. Also, TNF-RI^−/− mice were injected with RRV in the same manner as wild-type mice. In all cases, TNF inhibition did not reduce the severity or incidence of disease. Survival curves of mice given blocking agents were similar to those of control RRV-inoculated mice, and survival of challenged TNF-RI^−/− mice was worse than that of wild-type mice, likely because of the prolonged presence of infectious RRV. In all experimental groups, markers of disease were unchanged from those of control mice. In summary, although RRV-inoculated BALB/c mice have highly elevated expression of TNF-α, this cytokine does not play an obligate role in disease progression.