Background: To assess the joint and stratified associations between cardiorespiratory fitness (CRF), incidence, and mortality from cancer in never, former, and current male smokers. Methods: CRF (treadmill exercise test) was assessed in 4694 men (never smokers [n = 1715]; former smokers [n = 1602], 32.4 [30.5] pack-years; and current smokers [n = 1377], 40.3  pack-years) aged 58.1 (17.3) years, and prospectively followed for 12.7 (7.5) years. Multivariable Cox hazard models were analyzed. Results: In joint analyses, where high CRF in never smokers was used as a reference, hazard ratios and 95% (confidence intervals) for cancer incidence and cancer mortality were as follows: moderate CRF 1.41 (1.0–1.9) and 3.0 (1.7–5.5) in never smokers, 1.65 (1.3–2.2) and 3.7 (2.1–6.6) in former smokers, and 1.3 (0.9–1.7) and 3.4 (1.9–6.1) in current smokers, respectively. The corresponding values for low CRF were 1.53 (1.1–2.2) and 5.1 (2.7–9.5), 1.84 (1.3–2.5) and 6.6 (3.7–11.8), and 1.5 (1.1–2.2) and 5 (2.7–9.3), respectively. In stratified analyses by smoking status, compared with low CRF, moderate and high CRF were associated with a 32% to 78% reduction in cancer mortality risk (P trend for all <.001). Conclusion: Higher CRF is associated with lower risk of incidence and mortality from cancer regardless of smoking status, supporting the potential preventive benefits for public health.