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In contrast to the extensive amount of information available about their physical health, scientific knowledge about the mental well-being of professional footballers is scarce. In addition, the potential relation of musculoskeletal injuries with the mental well-being of professional footballers has not been studied yet.To explore the mental well-being (distress, anxiety depression, sleep disturbance, adverse alcohol use) of professional footballers over twelve months and to assess its relation with musculoskeletal injuries.Observational prospective cohort study with a follow-up period of twelve months was conducted.Professional football in five European countries: Finland, France, Norway, Spain and Sweden.A total of 540 professional footballers were enrolled (mean age at recruitment was 27 years; mean career duration was 8 years; 55% from the highest national level).The total number of time-loss (>4 weeks) injuries occurred during a player's career was examined by a single question.Distress, anxiety depression, sleep disturbance, adverse alcohol use were self-reported through validated scales.Among professional footballers, twelve-month incidence was 12% for distress, 37% for anxiety/depression, 19% for sleep disturbance and 14% for adverse alcohol use. At baseline, professional footballers who had sustained two or more time-loss injuries during their career were 2.5 to 3.5 times more likely to report distress, anxiety depression, sleep disturbance or adverse alcohol use.A professional football team typically drawn from a squad of 25 players can expect in one season at least three players to struggle with their mental well-being. This study empowers the need of an interdisciplinary approach to the clinical care and support in professional football.