Myeloma cells express the idiotype (Id)-specific antigen that may be targeted by Id vaccination. Six patients with stage I IgG myeloma were immunized with the autologous purified M component together with the adjuvant cytokines interleukin 12 (IL-12) alone or in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF). The effect of Id vaccination on circulating clonal tumor B cells was monitored by a real-time allele-specific oligonucleotide polymerase chain reaction method. No other treatment was given. Reduction of blood tumor mass was observed in 4 of 6 patients, with one patient achieving a complete molecular remission in blood. In 3 of these 4 patients an Id-specific T-cell response was induced. In the remaining 2 patients with an unchanged level of blood tumor cells, one patient mounted a T-cell response, whereas the other did not. No significant change in the serum M protein level was noted. Id vaccination may target clonal B cells, suggesting that this strategy might be conducive to achieving tumor control. The clinical significance of these findings remains to be established.