This study examined the antitumor properties of blood monocytes isolated from patients undergoing a phase I trial with liposomes containing muramyl tripeptide phosphatidylethanolamine (L-MTP-PE). Peripheral blood monocytes were isolated from 28 patients receiving twice weekly i.v. injections of escalating doses of L-MTP-PE. Monocytes were harvested before therapy and at various times during the 9-week treatment period. Activation of monocyte-mediated tumorilytic activity was found in 24 of the 28 patients at some time during treatment. Whereas the maximum tolerated dose of L-MTP-PE was 4-6 mg/m2, the optimal biological dose in terms of macrophage activation was 0.5-2.0 mg/m2. The spontaneous secretion of interleukin 1 from monocytes isolated pre- and postinfusion was monitored in two patients. In both patients interleukin 1 secretion correlated with the cytotoxic activity of the monocytes. We conclude that the systemic administration of L-MTP-PE can render the blood monocytes of cancer patients tumor cytotoxic. Since L-MTP-PE is an immunomodulator devoid of direct antiproliferative effects on tumor cells, the data suggest that future clinical trials be conducted using the optimal biological dose rather than the maximum tolerated dose.