Cognitive impairment is a common phenomenon in multiple sclerosis (MS), occurring at all stages of the disease, even at the earliest, and can be a major source of disability, social impairment, and impoverished quality of life. Cognitive dysfunction is mainly focused on working memory, conceptual reasoning, verbal fluency, speed of information processing, attention and executive function. Additional clinical factors, including disease course, fatigue and affective disturbance, can impact the degree of MS-related cognitive impairment. We present the results from the two-phases of our prospective study on cognitive decline in MS patients using the data collected from the A' Neurologic clinic at AHEPA hospital, Thessaloniki, Greece. Most of the patients of the present study revealed mild cognitive impairment with mild influence on the everyday function. We found weak correlation between cognitive deficit and the duration of MS, as well as the physical disability status and moderate correlation between cognitive impairment and the type of the disease as well as MRI findings (atrophy and lesion load). Our results also indicate that the currently available battery of neuropsychological tests: California Verbal Learning test (CVLT), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test and Paced Auditory Serial Addition Test (PASAT) can be used as a reliable tool in the diagnosis of cognitive deficits of MS patients, as related to their degree of disability and to the type of their disease. Evaluation of cognitive functions should be incorporated in the regular assessment and monitoring of MS patients since they seem to be well correlated with the progression of the disease.