Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by death of motor neurons leading to devastating muscle weakness and wasting and weight loss. It causes mixed picture of lower motor neuron (LMN) and upper motor neuron (UMN) dysfunction. The wide spectrums of atypical presentations can frequently lead to expensive work-up and undue delay in diagnosis of ALS. Occasionally, brain MRI of ALS patients shows some lesions in white matter. Moreover, cerebrospinal fluid (CSF) analysis demonstrates oligoclonal bands (OCB) in a few subjects. Because of the UMN signs, brain white matter lesions and presence of OCBs in CSF, ALS can be misdiagnosed as Multiple Sclerosis (MS).Also, some findings in ALS mimic central nervous system (CNS) vasculitis. We are reporting a case of ALS in a 48-year-old man presenting with subacute progressive spastic diparesis and brain white matter lesions which was initially misdiagnosed by MS and CNS vasculopathy.