Background <p>Cardiorespiratory fitness (CRF) is a common risk factor for cardiometabolic diseases, but the causal relation of CRF with chronic obstructive pulmonary disease (COPD) and its interplay with genetic risk remain unknown. We integrated genetic susceptibility and causal inference methods to evaluate the protective roles of CRF in COPD development.</p> Methods <p>We included 68,288 White British individuals from the UK Biobank (aged 40–79 years) without prevalent COPD at the baseline (2006–13). CRF was assessed using heart rate responses to submaximal bike tests. Genetic risk for COPD was quantified using a polygenic risk score constructed from 71 uncorrelated single nucleotide polymorphisms. Cox regression was used to estimate the hazard of COPD. Causal inference was evaluated via two-sample Mendelian randomisation (MR). Potential reverse causation was assessed using a bidirectional MR.</p> Results <p>Within an MR framework, we found that higher genetically predicted CRF is causally associated with lower risk of COPD. Observational analysis found: (1) compared with low CRF (bottom tertile), hazard ratios (95% CI) of COPD were 0.80 (0.72–0.89) and 0.71 (0.64–0.80) for medium and high CRF, respectively; (2) compared to the high CRF-low genetic risk group, COPD hazards were higher for individuals who had medium or high genetic risk combined with low or medium CRF but not for those who had medium genetic risk but high CRF; (3) low CRF combined with any levels of genetic risk showed consistently higher COPD hazards relative to high CRF and low genetic risk combination.</p> Conclusions <p>Being more aerobically fit may prevent or delay the onset of COPD. Improving CRF has the potential to attenuate the increased risk of COPD associated with elevated genetic risk. Public health initiatives should prioritise making measurable improvements in cardiorespiratory fitness (beyond merely being active or exercising more) as a promising intervention target for reducing the risk of COPD.</p>