Multiple sclerosis (MS) is a chronic inflammatory disease and may cause demyelination and axonal degeneration. Inflammation, an important factor underlying MS disease, occurs as a result of the interaction between demyelination and neurodegeneration. Physical, cognitive, and psychological disabilities are considered important factors in MS, which usually affects young adults. Multiple genetic variations play an important role in the patient’s clinical presentation, individual response to medications, disease progression, and disability. In MS, the cerebral cortex and the white matter of the spinal cord are affected. The clinical course of MS has a phase that initially involves inflammatory predominance and then progresses to neurodegenerative mechanisms. Although MS disease-modifying treatments are effective in the inflammatory phase, their effects on MS progression are not fully understood. The increased risk of developing MS, the aggressiveness of the disease in patients diagnosed with MS, and protective factors are genetic factors that are constantly being investigated. Obtaining more comprehensive information about the roles of genetic factors, such as disability-associated gene variations, in regulating the response to MS treatment is extremely important for the development of new therapeutic strategies in the treatment of the disease. The aim of this entry is to examine genetic variations associated with disability in MS based on the relationship between MS disease and disability.