Inclusion body myopathy (IBM) is a myopathy causing asymmetric proximal and distal limb muscle involvement in patients over 50 years. Motor neuron disease (MND) is a neurodegenerative disorder involving upper and lower motor neuron in the spinal cord and brainstem, characterized by progressive muscle weakness resulting in paralysis. The pathogenesis of cell injury in both diseases is still unknown: several hypothesis have been proposed addressing viral, autoimmunity, genetic and oxidation stress factors. We report on 2 cases with clinical presentation of upper and/or lower motor neuron involvement and histopathological diagnosis of IBM. Case 1: a 68 years old man with an 18‐month history of progressive weakness, spasticity, dysarthria, dysphagia. Neurological examination showed generalized muscle weakness, wasting of the finger flexors and quadriceps, fasciculations, deep tendon hyperreflexia. Electromyography (EMG) showed neurogenic signs and fasciculations at limbs and tongue muscles. Nerve conduction studies showed reduced cMAP amplitude at the legs, Motor Evoked Potential (MEP) revealed marked pyramidal tract involvement. Blood examination showed increased E.S.R. with normal level of serum creatinine kinase, copper, ceruloplasmin, and iron. Antiganglioside antibodies titer was normal and blood lactate analysis showed normal values during exercise. Cerebrospinal fluid (CSF) examination showed increased protein level. Brain magnetic resonance imaging disclosed of involvement of the cortico‐spinal tract and deposits of paramagnetic material in the basal ganglia with normal dopaminergic receptorial SPECT binding. Muscle biopsy revealed a neurogenic myopathy with “rimmed vacuoles”. Case 2: a 64 years old woman with 20 month history of muscle weakness slowly progressing from upper to lower limbs. Neurological examination showed distal muscle weakness and wasting at the upper limbs, deep tendon hypo‐areflexia. EMG showed neurogenic signs and fasciculations at four limbs. MEP and nerve conduction studies were normal but H reflex and F late responses were absent. E.S.R. was increased, while antiganglioside antibodies titer, thyroid hormones dosage and CSF examination were normal. Muscle biopsy revealed a neurogenic myopathy with rare “rimmed vacuoles”. These case reports, although not nosologically defined, confirm the clinical variability of the IBM and rise questions on the possible mechanisms of neuronal damage in motor neuron syndromes.