Endotoxin and the lipid-A portion of the molecule have a variety of biological effects, including the induction of necrosis and regression of malignancy. To date extensive clinical trials of endotoxin as a potential therapeutic agent have been shunned due to the toxicity of the material. Several lipid-A analogues have been described which have reduced toxicity and retain antitumor activity. We have investigated in a phase-I trial the clinical toxicity and immunological effects of monophosphoryl lipid A prepared from Salmonella typhimurium and Salmonella minnesota. Patients entered on the study received IV monophosphoryl lipid A twice weekly for a total of 4 weeks. At least three patients were entered sequentially at each of the dose levels of 10, 25, 50, 100, and 250 micrograms/m2 body surface area. One patient was treated at the dose level of 500 micrograms/m2. The major clinical toxicity was fever, chills, and rigor, which occurred in over 50% of the treatments at doses of 250 micrograms/m2. Two instances of bronchospasm occurred in one patient who received 250 micrograms/m2. One patient received 500 micrograms/m2 and became hypotensive. Sequential clinical data showed no evidence of renal or hepatic toxicity. A transient decrease in the WBC and platelets occurred during the first 24 h after therapy. Immune function testing measured T cells, monocyte cytostasis, monocyte suppressor cell activity, and NK activity. These data suggested a shift in monocyte populations with activated cells moving into the tissue. Direct objective antitumor activity or necrosis was not observed in this group of patients. We conclude that monophosphoryl lipid A can be given to patients in a dose of up to 100 micrograms/m2 with acceptable toxicity. Its clinical activity as a single agent in combination with other immunomodulators remains to be demonstrated.