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Hepatocyte growth factor is an endogenous pleiotropic factor shown to act as a potent neuroprotectant against disease progression in animal models of amyotrophic lateral sclerosis, which is a devastating, adult‐onset motor neuron disease. To evaluate the safety, tolerability, and pharmacokinetics of recombinant 5‐residue‐deleted human hepatocyte growth factor (KP‐100) injected intrathecally through an implantable catheter connected to a subcutaneous port, we conducted a first‐in‐human phase I trial of intrathecal KP‐100 in 15 Japanese patients with amyotrophic lateral sclerosis. The regimen was a single injection of 3 escalating doses (0.2, 0.6, and 2.0 mg/body) in 9 subjects followed by 2 doses (0.6 and 2.0 mg/body) repeated 5 times at 1‐week intervals in 6 subjects (3 subjects/group). With single‐dose administration, the mean half‐life of KP‐100 in the cerebrospinal fluid was 1.2 to 1.4 days, with its maximum concentration increasing in a dose‐dependent manner. With multiple‐dose administration, the trough KP‐100 concentrations in the cerebrospinal fluid generally remained constant for any dose, despite multiple dosing. There were no deaths, serious adverse events, or device malfunctions leading to discontinuation. In all subjects, plasma KP‐100 concentrations were <1 ng/mL, or below the lower limit of detection at all time points of measurement. Anti–KP‐100 antibody was not detected in the cerebrospinal fluid or plasma specimens from any of the subjects throughout the KP‐100 dosing period. These results suggest that KP‐100, as well as the device used to administer it, is safe and tolerable. A phase II trial is warranted in patients with various central nervous system diseases such as amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]