Interleukin-6 (IL-6) is a potent immunomodulatory cytokine that may have pathogenetic and prognostic significance in a number of disorders. The objective of this study was to examine the correlation between serum IL-6 levels and phenotypic characteristics, as well as failure-free survival of patients with low-grade non-Hodgkin's lymphomas (NHL). Using a sensitive enzyme-linked immunoabsorbent assay (ELISA), we measured IL-6 in frozen sera from 55 healthy controls and in the pre-treatment frozen sera from 100 low-grade lymphoma patients who were enrolled on protocols at MD Anderson Cancer Center. Serum IL-6 levels were correlated with clinical and laboratory features at diagnosis and with failure-free survival. The serum IL-6 levels were > or =2 pg/mL in 9% (median, <0.91 pg/mL; range, <0.91-4.31 pg/mL) of controls versus 25% of the indolent lymphoma patients (median, <0.91 pg/mL; range <0.91 to 225.97) (p = 0.0118). Serum IL-6 levels were higher in patients with B-symptoms (p = 0.02), an elevated P2-microglobulin level (> or =3.0 mg/L) (p = 0.00013), and unfavorable International Index (p = 0.03). Patients with elevated serum IL-6 levels had an inferior failure-free survival (log rank p = 0.008) compared with those with normal serum IL-6 levels (three-year-failure-free-survival = 55% versus 81%, respectively). In conclusion a minority (25%) of patients with indolent non-Hodgkin's lymphomas have elevated serum levels of IL-6 at diagnosis. In these individuals, high IL-6 levels are associated with adverse disease features, and predictive of a shorter failure-free survival.