Hepatitis C virus (HCV) infection results in robust anti-viral antibody responses, but often fails to clear the virus, resulting in chronic infection. HCV infection is also frequently characterised by the production of autoantibodies including rheumatoid factors. Some rheumatoid factors are soluble, whilst others develop the unusual characteristic of becoming insoluble at low temperatures, referred to a cryoglobulins. These may precipitate within small vessels and cause cryoglobulinaemic vasculitis. Separately, patients with hepatitis C infection are at increased risk of non-Hodgkin’s lymphoma, with cryoglobulinaemia being a risk factor, although the reasons for this are not fully understood. We utilise single-cell genomic and proteomic analysis of B cells in chronically infected HCV patients with cryoglobulinaemic vasculitis, to characterise the progression of B cells from their origins as anti-viral responders through to autoreactive B cells that develop somatic DNA mutations in lymphoma driver genes, the harbinger of lymphomagenesis.