A causal link among hepatitis C virus (HCV) infection and essential mixed cryoglobulinemia, cryoglobulinemic glomerulonephritis, and vasculitis is strongly supported. HCV triggers autoimmune response in predisposed individuals that manifests as organ-specific and non-organ-specific autoantibodies and as polyclonal/monoclonal rheumatoid factor, which has a central role in causing damaging cryoglobulin and immune complex tissue levels. Immunologic events are mainly induced by HCV infection persistence, with excessive immune stimulation. Humoral immune dysfunction leads to autoantibodies and rheumatoid factor production with cryoglobulinemia, glomerulonephritis, vasculitis, neuropathy, and probably thyroiditis, and arthritis in rare cases. Cellular immune dysfunction leads to lymphocytic infiltration, proliferation, and cytokine production. Pegylated (or not) interferon-alpha in combination with ribavirin appears to be the treatment of choice for patients with symptomatic essential mixed cryoglobulinemia with or without glomerulonephritis. Novel treatment with rituximab is promising.