The growth stimulatory effects of interleukin-3 (IL-3) on normal hematopoietic progenitor cells are well established, and clinical trials using IL-3 after bone marrow transplantation for various malignancies including lymphomas are frequently conducted. Although the IL-3 receptor is expressed on the surfaces of follicular small cleaved-cell lymphoma (FSCCL) cells, the in vivo effects of IL-3 on FSCCL have not been studied previously. Because our preclinical data suggested that IL-3 may have dose-dependent inhibitory effects on FSCCL cells in vitro, we treated eight FSCCL patients with high-dose IL-3 in an outpatient setting. Each patient received 1 mg/m2 of IL-3 subcutaneously daily for 14 days followed by 7 days without IL-3. After three courses (9 weeks), the patients were evaluated for clinical responses. One patient had a minor response, and four had no responses. Three patients who had progressive disease before IL-3 treatment continued to have progressive disease. In two patients with bone marrow involvement with lymphoma, IL-3 had no effect on FSCCL cells. One patient with peripheral blood involvement with FSCCL cells that expressed IL-3 receptors had temporary growth arrest of the circulating malignant cells. IL-3 significantly increased the absolute neutrophil count in seven patients (87%) but had little effect on the number of normal circulating B cells. There was an increase in the number of circulating natural killer cells and CD8+ cells in four patients. Treatment was very well tolerated; no life-threatening toxicities were observed. The most common toxicities were injected conjunctivae (100%), fever (100%), fatigue (87%), and skin rash (75%). Most of the side effects subsided with the continued use of IL-3. These preliminary results suggest that high-dose IL-3 does not stimulate the growth of FSCCL cells in vivo and, in some instances, may cause growth inhibition.