Hepatitis C virus (HCV) is associated with the B-cell lymphoproliferative disorders mixed cryoglobulinemia (MC) and non-Hodgkin lymphoma. We have previously reported that HCV(+)MC(+) patients have clonal expansions of hypermutated, rheumatoid factor-bearing marginal zone-like IgM(+)CD27(+) peripheral B cells using the V(H)1-69 gene. Here we coupled transcriptional profiling with immunophenotypic and functional studies to ascertain these cells' role in MC pathogenesis. Despite their fundamental role in MC disease, these B cells have overall transcriptional features of anergy and apoptosis instead of neoplastic transformation. Highly up-regulated genes include SOX5, CD11C, galectin-1, and FGR, similar to a previously described FCRL4(+) memory B-cell subset and to an "exhausted," anergic CD21(low) memory B-cell subset in HIV(+) patients. Moreover, HCV(+)MC(+) patients' clonal peripheral B cells are enriched with CD21(low), CD11c(+), FCRL4(high), IL-4R(low) memory B cells. In contrast to the functional, rheumatoid factor-secreting CD27(+)CD21(high) subset, the CD27(+)CD21(low) subpopulation exhibits decreased calcium mobilization and does not efficiently differentiate into rheumatoid factor-secreting plasmablasts, suggesting that a large proportion of HCV(+)MC(+) patients' clonally expanded peripheral B cells is prone to anergy and/or apoptosis. Down-regulation of multiple activation pathways may represent a homeostatic mechanism attenuating otherwise uncontrolled stimulation of circulating HCV-containing immune complexes.