Therapy for cancer patients with biologically active immune modulators is attractive but has met with limited clinical success. Interleukin-2 (IL2) stimulates T-cells and natural killer (NK) cells to kill tumor cells and levamisole (LMS) is an immunostimulant which has been shown to increase NK cells and activated T-cells in patients receiving this adjuvantly along with 5FU for Stage III colon cancer. This study was designed to evaluate whether treatment with LMS prior to IL2 would provide synergistic activity and improve response rates. Four patients with advanced malignancies were treated with LMS at 50 mg p.o. TID for 3 days followed on day 4 with 600,000 units/kg IL2 as a single i.v. bolus. This treatment was repeated weekly until progression. Serum soluble IL2 receptor (sIL2R) and interferon-gamma levels were monitored throughout the treatment course as markers of immune activation. All patients had eventual progression of disease. Toxicity was minimal with Grade II orthostatic hypotension the major consequence of therapy. The pattern of sIL2R levels in 3/4 patients revealed a steady increase over the several weeks of therapy, indicating ongoing immunostimulation (r=0.53 , p=0.001). Short-term treatment with LMS, however, resulted in a significant and consistent decreases in sIL2R levels (2198 U/ml vs. 1969 U/ml, p=0.001) in all patients. In conclusion, LMS/IL2 in the dose and schedule utilized here was not clinically effective. However, LMS reduced sIL2R levels immediately following a three-day course. This reduction in sIL2R by LMS may improve the possibility of response to IL2 by facilitating a decrease in inhibitory sIL2R. Combinations of these two agents should continue to be investigated as potential synergistic anti-tumor agents.