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Sickness absence from work has a large adverse impact on both individuals and societies in Sweden and the costs for sickness absence were calculated to 64.6 billion Swedish kronor (approx. 5.6 billion in Euros) in 2020. Although high cardiorespiratory fitness may protect against potential adverse effects of high physical workload, research on the moderating effect of respiratory fitness in the relation between having an occupation with high physical workload and sickness absence is scarce. To study the moderating effect of cardiorespiratory fitness in the association between occupation and psychiatric, musculoskeletal, and cardiorespiratory diagnoses. Data was retrieved from the HPI Health Profile Institute database (1988–2020) and Included 77,366 participants (mean age 41.8 years, 52.5% women) from the Swedish workforce. The sample was chosen based on occupational groups with a generally low education level and differences in physical workload. Hurdle models were used to account for incident sickness absence and the rate of sickness absence days. There were differences in sickness absence between occupational groups for musculoskeletal and cardiorespiratory diagnoses, but not for psychiatric diagnoses. In general, the association between occupation and musculoskeletal and cardiorespiratory diagnoses was moderated by cardiorespiratory fitness in most occupational groups with higher physical workload, whereas no moderating effect was observed for psychiatric diagnoses. The study results encourage community and workplace interventions to both consider variation in physical workload and to maintain and/or improve cardiorespiratory fitness for a lower risk of sickness absence, especially in occupations with high physical workload.