T cells contribute to host-tumor interactions in patients with monoclonal gammopathies. Expansions of CD8+CD57+ T-cell receptor Vβ-positive (TCRVβ+)-restricted cytotoxic T-cell (CTL) clones are found in 48% of patients with multiple myeloma and confer a favorable prognosis. We now report that CTL clones with varying TCRVβ repertoire are present in 70% of patients with Waldenström macroglobulinemia (WM; n = 20). Previous nucleoside analog (NA) therapy, associated with increased incidence of transformation to aggressive lymphoma, significantly influenced the presence of TCRVbeta expansions (Χ2 = 11.6; P <.001), as 83% of patients without (n = 6) and only 7% with (n = 14) TCRVβ expansions had received NA. Clonality of CD3+CD8+CD57+TCRVβ+-restricted CTLs was confirmed by TCRVβ CDR3 size analysis and direct sequencing. The differential expression of CD3+CD8+CD57+TCRVβ+ cells was profiled using DNA microarrays and validated at mRNA and protein level. By gene set enrichment analysis, CTL clones expressed not only genes from cytotoxic pathways (GZMB, PRF1, FGFBP2) but also genes that suppress apoptosis, inhibit proliferation, arrest cell-cycle G1/S transition, and activate T cells (RAS, CSK, and TOB pathways). Proliferation tracking after stimulation confirmed their anergic state. Our studies demonstrate the incidence, NA sensitivity, and nature of clonal CTLs in WM and highlight mechanisms that cause anergy in these cells.