Aim:To study how change in cardiorespiratory fitness over time is associated with the development of poor self-rated health in healthy Swedish adults, and whether this association varies with sex, age, body mass index and cardiorespiratory fitness at baseline. A secondary aim was to study the influence of other predictors of self-rated health.Methods:A total of 98,718 participants (45% women, mean age 42.2 years) with two assessments from occupational health service screenings between 1988 and 2019 (mean duration 4.3 years), with good self-rated health at baseline were included. Cardiorespiratory fitness was assessed as estimated maximal oxygen consumption using submaximal cycle testing. Change in cardiorespiratory fitness was expressed as percentage annual change. Poor self-rated health at follow-up was defined as percieving self-rated health as ‘poor’ or ‘very poor’.Results:A large decrease in cardiorespiratory fitness (⩾−3%) was associated with a 34% higher risk of poor self-rated health compared to maintainers (−1 to +1%) after multi-adjustment including change in body mass index, back/neck pain, stress, exercise habits and sleep quality or sleep problems. The associations for decreasers were stronger with longer follow-up time (>10 years). Preserving, or changing to, risk level for body mass index, back/neck pain, stress, exercise and sleep quality/problems were associated with a higher risk of poor self-rated health.Conclusions:Preserving or increasing cardiorespiratory fitness is associated with a lower risk of poor self-rated health, independently of change in other health-related variables, which may act as a protection against future poor self-rated health. This is of high clinical value, and strategies for maintaining or improving cardiorespiratory fitness have the potential to influence both disease and mortality.