We have investigated the ability of levamisole (LMS) to modulate growth and metastasis of a rat hepatocarcinoma. LMS treatment decreased spontaneous metastasis to the lungs and lymph nodes, while it increased tumor lung colonization following intravenous tumor cell inoculation. Both serum immunoglobulin (Ig) and circulating immune complex (CIC) levels were higher than normal in tumor-bearing rats. LMS treatment did not alter these parameters in the lung colony assay, while a small decrease of serum IgG was noted for LMS treated animals in the spontaneous metastasis assay. We found no convincing evidence for CIC levels, immunoglobulin isotype shifts or induced changes in natural killer (NK) cell reactivity being involved in the observed LMS modulation of tumor metastasis. The nature of the presentation of the tumor in the animal, however, appeared to be critical in determining the metastatic response to LMS therapy.