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Fatigue is an important factor affecting sporting and mental performances. It is complicated process which includes peripheral and central components. Central fatigue occurs in central nervous system as a result of mental as well as physical activity. There are evidences that serotonin is implicated in central fatigue development. Serotonin turnover in the brain increases in response to physical exercise. Decreased motivation, tiredness, loss of motor coordination - markers of central fatigue, are associated with the rise of brain serotonin concentration. But the role of serotonin in the development of mental fatigue is unclear. In the current study we investigate associations of serotonin system genes polymorphism with the mental fatigue. In the study students of Moscow State University took part (N=160, male=78, female=82). Volunteers were exposed to intensive mental workload (logical tasks and monotonous persistent completion of psychological tests) during 3 hours. Before and after workload the psychophysiological state was estimated with the help of “NS-Psychotest” (Neurosoft, Russia). Additionally volunteers completed self-ratings of mental fatigue and of functional state. It was detected that carries of both ss-genotype of the 5HTTLPR and CC-genotype of the 5-HT2A polymorphism (T102C) reported higher level of mental fatigue after performing fatigue task compared with carries of ll(5HTTLPR) genotype and of TT(T102C) genotype. ss-genotype of the 5-HTTLPR as well as CC-genotype of the 5-HT2A are associated with reduced expression of both genes and therefore could cause increasing concentrations of extracellular serotonin in the brain. These findings suggest a role of serotonin transmission efficiency in mental fatigue.