Delayed and variable antibody responses to HCV make it difficult to diagnose acute HCV infection reliably. Immunoglobulin (Ig)M and IgG anti-HCV may be observed simultaneously as disease persists. IgM plays a key role in mixed cryoglobulinemia (MC), an immune complex disease strongly associated with persistent HCV infection. In MC, clonal or oligoclonal IgM rheumatoid factors facilitate the deposition of immune complexes in small blood vessels and tissue, leading to inflammation, complement activation and tissue damage. Clonally expanded IgM(+)κ(+) B-cells expressing rheumatoid factor-like IgM are abundant in many HCV patients with MC. The observation that identical or similar IgM antibodies are expressed in different patients' clonally expanded B-cells supports the hypothesis that MC is driven by antigen-specific B-cell activation, rather than polyclonal B-cell activation or HCV replication in B-cells. More study is required to identify the antigens that drive the development of MC.