Interleukin-2 (IL-2) is a cytokine that became available for clinical use with the development of recombinant DNA technology. Patients with resistant or relapsed lymphoid neoplasm have been treated with high-dose IL-2 with some responses. The aim of the present study is to determine whether there may be a biological justification for the use of low dose subcutaneous (s.c.) IL-2 as maintenance therapy in patients with lymphoid neoplasm in complete remission with high risk of relapse. We treated 15 patients with sc IL-2, 4.5 Million International Units (MIU) daily, 5 days per week for 12 consecutive weeks, in the outpatient clinic. This therapy was well tolerated and could be administered in an outpatient regimen. It increased the eosinophil count (p = 0.009), but the number of granulocytes, monocytes, T-lymphocytes and B-lymphocytes did not change. The number of natural killer (NK) cells increased from 11% to 35% of all lymphocytes during IL-2 therapy (p = 0.0006). Effector lymphokine-activated killer activity (eLAK) also increased from 6x10(-3) Lytic Units (LU)/ml to 80x10(-3) LU/ml (p = 0.02). All these changes reached a "plateau" after the 4th week of therapy. The increase in the number of NK cells correlated strongly with the increase in eLAK activity (r = 0.96, p<0.0001). Disease-free survival was determined in 14 patients who completed the treatment and compared with historical controls. Patients treated with IL-2 had the same relapse risk (median time to relapse 11.1 months, 95% confidence interval 5.5-16.6) as did controls (median time to relapse 9.7 months, 95% confidence interval 1-27.7) (p = 0.9). Low dose s.c. IL-2 stimulated NK proliferation, which generated cytotoxic activity in vivo in patients with lymphoid neoplasms. However, these patients did not have a lower risk of disease relapse compared to historical controls.