In the wobbler mouse motor neuron disease (MND), we firstly evaluated the effect of riluzole, the only approved drug for amyotrophic lateral sclerosis, and compared it with that of brain-derived neurotrophic factor (BDNF). Wobbler mice received either daily subcutaneous treatment with BDNF (5, 20, and 40 mg/kg) or oral riluzole in drinking water (100 and 200 microg/ml), beginning immediately after the clinical onset of MND. We examined motor functions, such as grip strength and rota-rod walking performance, weekly, and the amplitude of the compound muscle action potential (CMAP) in the forelimb biceps at the end of treatment. BDNF treatment slowed the disease progression maximally at a dose of 20 mg/kg, consistent to the previous evidence. Only high-dose riluzole treatment increased grip strength at weeks 1 (P=0.0023) and 2 (P=0.021), time before falling in the rota-rod test throughout all 4 weeks of treatment (P=0.0022 to 0.0282), and CMAP amplitude (P=0.0069) at the end of treatment, compared with the vehicle. Furthermore, the riluzole treatment increased the number of the cervical cord anterior horn neurons that were immunoreactive for SMI-32, a specific motor neuron marker, by the end of treatment (P=0.0063), although it did not affect the vacuolar degeneration on the SMI-32-positive neurons. This study demonstrated that riluzole was comparable to BDNF in slowing the progression of neuromuscular dysfunction in the wobbler mouse MND, which may provide a useful model for examining the mechanisms of selective motor neuron degeneration.