Aims To investigate the association between high occupational physical workload in mid-life and subsequent ischaemic heart disease (IHD), and if this association is influenced by cardiorespiratory fitness assessed in youth.Methods and results A total of 284 436 men, born 1951-61, were compared in terms of occupational physical workload assessed with a job exposure matrix in 2005 (age 44-54) and followed up regarding IHD incidence and mortality, between 2006 and 2020 (age 45-69). Cardiorespiratory fitness in youth was assessed during military conscription, using a maximal cycle test. Cox regression and additive interaction modelling, using the synergy index (SI), were applied. High occupational physical workload in mid-life was associated with an increased risk of incident IHD [hazard ratio (HR) 1.34, 95% CI 1.29-1.39] and IHD mortality (HR 1.93, 95% CI 1.75-2.14), compared to having low occupational physical workload. The associations attenuated with adjustments for early life factors, e.g. socioeconomic position, body mass index, blood pressure, and highest attained education. However, they remained statistically significant; HR 1.06 (95% CI 1.02-1.11) for incident IHD and HR 1.38 (95% CI 1.23-1.55) for IHD mortality. Having both low cardiorespiratory fitness in youth and later high physical workload showed the highest risk, indicating an additive interaction, but the SI was non-significant.Conclusion High occupational physical workload in mid-life was associated with increased risks of IHD incidence and mortality. The combination of low fitness and high workload showed the highest risks. These results encourage both workplace and public health interventions for variation in occupational physical workload and improvement in cardiorespiratory fitness. This large observational study showed that exposure to high occupational physical workload in mid-life was associated with an increased risk of ischaemic heart disease (IHD) incidence and mortality, and the associations were strongest when high occupational physical workload was combined with low cardiorespiratory fitness assessed in youth.High occupational physical workload in mid-life, compared to low physical workload, was associated with an increased risk of incident IHD and IHD mortality, even when accounting for several potential confounders. The strongest association was seen for IHD mortality.The combination of having low cardiorespiratory fitness in youth and later high occupational physical workload was associated with the highest risk of both incident IHD and IHD mortality. In addition, it could be seen that low cardiorespiratory fitness in youth was more common among those who later had physically demanding occupations.