Retrospective assessment of hepatic and central nervous system involvement associated with chickenpox cases at a large metropolitan medical center reveals that 28 of 58 patients had biochemical, but not inflammatory, evidence of liver involvement. An additional 18 patients had biochemical liver abnormalities along with non-inflammatory encephalopathy (Reye syndrome) and 12 had clear evidence of central nervous system inflammatory involvement (encephalitis). There were no cases of solitary inflammatory liver involvement. Reviewed evidence suggests that the pathogenesis of hepatopathy and hepatoencephalopathy (Reye syndrome) is not caused by replication of virus in the involved organs, but instead is mediated through a cytotoxic mechanism and that the inflammatory brain disease is also not caused by viral replication in brain tissue, but appears to be tissue damage associated with immune cell responses (post-infectious encephalitis). The concept put forth in this essay is that a virus replicating in one organ (skin) could affect the macromolecular function of cells in another organ (liver, brain) bringing about both hepatopathy and hepatoencephalopathy.