Valosin Containing Protein (VCP) gene mutations have been reported in ~1-2% of familial amyotrophic lateral sclerosis (ALS). We report a case of clinically defined and neuropathologically confirmed ALS in a 48-year-old, emaciated female with a p.R155C (c.463 C > T) mutation in VCP gene. She presented with progressive generalized muscular weakness, weight loss, dyspnea on exertion, combined nasal and spastic dysarthria, positive jaw jerk and exaggerated gag reflex. Electrodiagnostic studies revealed involvement of both upper and lower motor neuron typical of generalized ALS. She died of fulminant ALS three years after onset of clinical features. Neuropathological examination revealed extensive spinal motor neuron degeneration with loss of spinal anterior horn cells, gliosis and mislocalization of TDP-43 positive inclusions. Bilateral lateral columns showed degeneration. No abnormalities were detected in the brainstem and cerebellar hemispheres except for occasional intraneuronal vacuolation in the medullary nuclei and Bunina bodies in the hypoglossal nucleus.