In solid tumors, leukemias, and lymphomas, increased frequencies of functional CD4⁺CD25^high regulatory T cells (T_reg cells) have been previously demonstrated. In healthy individuals, T_reg cells consist not only of memory but also of naive T cells, which can undergo peripheral expansion and are characterized by a relative enrichment for autoreactive T-cell receptors. Here, we demonstrate in patients with premalignant monoclonal gammopathy of undetermined significance and patients with multiple myeloma that functional FoxP3⁺ T_reg cells of naive, central, and effector memory phenotype as determined by CCR7 and CD45RA expression are significantly expanded. Low frequencies of T-cell receptor excision circles in naive T_reg cells in both healthy controls and multiple myeloma patients point to peripheral expansion as the prominent mechanism of increased frequencies of naive T_reg cells in these cancer patients. These findings strongly suggest that the increase of functional T_reg cells in cancer patients is a response to the process of malignant transformation.