The serum levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), soluble interleukin-2 receptor (sIL-2r), and interleukin-1alpha (IL-1alpha) were measured in 30 healthy subjects, 22 patients with monoclonal gammopathy of undetermined significance (MGUS), five patients with smoldering multiple myeloma (SMM), and 46 with multiple myeloma (MM). Serum levels of IL-6, TNF-alpha, and sIL-2r were significantly increased in patients with active MM when compared with normal controls. Furthermore, MM patients with advanced aggressive disease had significantly higher levels of IL-6, TNF-alpha, and sIL-2r than those with MM in plateau phase. In conclusion, our data support the involvement of IL-6, TNF-alpha, and sIL-2r in MM. This confirms recent in vitro studies suggesting that these cytokines may play a central role in the pathogenesis of MM. Our data also show that serum levels of TNF-alpha, sIL-2r, and, particularly, IL-6 could be useful in the clinical management of patients with MM.