Live-attenuated vaccines provide robust immunity against diseases like tuberculosis, measles, mumps, rubella, polio, yellow fever, dengue, typhoid fever, and varicella, with just one or a few doses. However, concerns arise regarding potential pathogen reversion to virulence, which is particularly risky for immunocompromised individuals, contraindicating their administration in multiple sclerosis (MS) patients under modified disease treatments due to the possibility of triggering infections, or stimulating the immune system, precipitating new exacerbations. On the contrary, these vaccines offer enduring immunity that is crucial for protecting MS patients from endemic infectious diseases, leading to severe complications if contracted. These concerns underscore the complex balance between vaccination benefits and the risks of exacerbating MS in patients residing in regions with endemic diseases. This review explores the challenges and considerations associated with their use in MS patients, aiming to maximize benefits while minimizing risks.