The role of hepatitis C virus (HCV) infection in the induction of type II mixed cryoglobulinemia (MCII) and the possible establishment of related lymphoproliferative disorders, such as B-cell non-Hodgkin lymphoma (B-NHL), is well ascertained. However, the molecular pathways involved and the factors predisposing to the development of these HCV-related extrahepatic complications deserve further consideration and clarification. To date, several host- and virus-related factors have been implicated in the progression to MCII, such as the virus-induced expansion of selected subsets of B-cell clones expressing discrete immunoglobulin variable (IgV) gene subfamilies, the involvement of complement factors and the specific role of some HCV proteins. In this review, we will analyze the host and viral factors taking part in the development of MCII in order to give a general outlook of the molecular mechanisms implicated.