Phenotypic characterization of peripheral blood lymphocytes was performed in patients with advanced metastatic cancer receiving low-dose recombinant interleukin-2 (rIL-2) and recombinant interferon-α (rIFN-α) as subcutaneous home therapy. A total of 31 patients with progressive metastatic renal cell carcinoma, malignant melanoma, colorectal cancer, B-cell lymphoma, and Hodg-kin’s disease, were evaluated. Patients were treated with a combination of low-dose subcutaneous rIL-2 and rIFN-α, consisting of a 2-day rIL-2 pulse at 9.0 million IU/m2 twice daily, followed by 6 weeks of combined low-dose rIL-2 at 1.8 million IU/m2 twice daily, 5 days per week, and rIFN-α at 5.0 million U/m2 3 times per week. This treatment regimen resulted in an overall significant (p < 0.002) increase in peripheral blood lymphocyte subsets expressing CD3, CD8, CD16, CD25, and CD56. Expansion of peripheral blood natural killer (NK) cells was correlated to treatment response. Thus, treatment-related increase in CD56-positive lymphocytes was 1.8-fold higher in complete or partial responders when compared to progressive disease patients (p = 0.0). Increase in NK cells upon low-dose rIL-2 and rIFN-α was associated with a significant expansion (p = 0.0) of peripheral blood eosinophils (r = 0.71). Patient pretreat-ment using rIL-2, rIL-2 and rIFN-α, or chemotherapy abrogated the treatment-induced induction of NK cells and IL-2 receptor- (CD25) positive T lymphocytes, respectively. Peripheral blood NK cells were significantly decreased (p < 0.05) in patients developing neutralizing antibodies specific t