Hairy cell leukemia (HCL) is a well recognized indolent B-cell lymphoproliferative disorder. HCL cell proliferation is regulated by growth factors and cytokines, of which tumor necrosis factor-alpha (TNF-alpha) may be one of the most important. The mechanism of TNF-alpha-induced HCL cell growth is mediated via 2 receptors, which are present in both cellular and soluble forms. In this study we determined the serum levels of TNF-alpha and their soluble receptors - sTNF-R60 and sTNF-R80 - in 23 HCL patients and correlated them with clinical parameters before and after therapy. Patients were classified according to their clinical status as either "active" at diagnosis or during relapse and "non-active" (responding to therapy with partial and complete remission). Most patients were treated with 2-CDA, following which serum levels of TNF-alpha, sTNF-R60 and sTNF-R80 were significantly decreased, particularly in CR. Significant differences in paired observation values were noted for TNF-alpha and sTNF-R80, indicating a good correlation with the clinical status of disease, but this was not the case for sTNF-R60 (coefficients of correlation between levels of TNF-alpha and sTNF-R80 and of TNF-alpha and sTNF-R60 were r = 0.85 and r= 0.64, respectively). These results suggest that decreases in both TNF-alpha and sTNF-R80 are indicative of response to treatment, while increased levels accompany active disease. Accordingly, we conclude that serum levels of the TNF family, as for the sIL-2R and IL-1 family, may also be used as sensitive markers for monitoring HCL status. Levels may be indicative of the clinical efficacy of therapy and can be used as an indicator of the presence of residual disease.