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Taking the analogy of peripheral neuromuscular fatigue, central fatigue may be defined as the failure to initiate and/or sustain attention tasks (‘mental fatigue’) and physical activities (‘physical fatigue’) requiring self motivation. Present study focuses on revelation the role of serotoninergic system on developing central fatigue under mental and physical performance. In order to carry out mental tasks, unrelated individuals, students of Moscow State University (N=158, male=73, female=85, mean age = 20) were recruited. The investigation of fatigue under physical activity was realized on athletes (N=74, male =44. female = 30). The study was performed in compliance with the standards established by the local ethics committee. All the participants gave written informed consent. MSU students were subjected to 3-hours-long fatigue-inducing mental tasks, such as logical problem solving and persistent monotonous completion of 30 psychological tests. Athletes performed physical performance on running-track during 1,5 hour. Before and after workload the state was estimated with the help the self-ratings of fatigue (The Mental Fatigue Inventory and Physical Fatigue Inventory) and Questionnaire of state of health, activity, mood. Also aggressiveness, anxiety and personality traits (openness, conscientiousness, extraversion, agreeableness, and neuroticism) were defined by Buss-Durkee Hostility Inventory (BDHI), Spielberg State-Trait-Anxiety Inventory (STAI) and “Big Five” Personality test correspondingly. There was a significant gender effect of 5-HTTLPR on state of health, activity, mood and also feeling of fatigue after performing mental and physical tasks. Analysis revealed that the males with two copies of LL allele were sensitive to fatigue then other genotypes carriers. Among females there were no significant differences between carriers of 5-HTTLPR. Also it was shown that gender influences on 5-HTTLPR association with aggressiveness, anxiety and personality traits. Women with two copies of LL had higher scores on verbal aggression and negativism and lower scores on anxiety compared with other genotypes carriers. Quite the contrary the most aggressive and less anxious men founded among carries of S allele (S=ss and ls carriers). The possible mechanism of gender differences related to the function of the serotonergic system and the 5-HTT gene are discussed.