Fifty-seven patients with amyotrophic lateral sclerosis (ALS) were randomly assigned to receive 0.5, 1, 3, 7, 10, or 30 μg/kg recombinant human ciliary neurotrophic factor (rHCNTF) or placebo subcutaneously 3 times a week for 2 weeks. Dose-limiting toxicity, consisting of febrile reactions in some patients, fatigue, and nonproductive cough, was observed at a dose level of 30 μg/kg. Dose-related changes in parameters of the acute-phase response were noted, consistent with the relationship of CNTF and its receptor system to the cytokine interleukin-6 (IL-6) and its receptor. No adverse neurologic consequences of rHCNTF administration were observed. Antibodies to rHCNTF were observed in sera of most patients tested after 2 weeks of continuous treatment and 4 weeks' withdrawal period. rHCNTF was safe and tolerated within acceptable limits when administered to patients with ALS in this study at doses of up to 30 μg/kg 3 times a week for 2 weeks. Further studies to explore the efficacy of rHCNTF in the treatment of human motor neuron diseases are justified.