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_H1-69 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. This study was registered at www.clinicaltrials.gov as #NCT00435201.