Although higher levels of physical activity are inversely associated with risk of colon cancer, few prospective studies have evaluated overall digestive system cancer mortality in relation to cardiorespiratory fitness (CRF). The authors examined this association among 38,801 men ages 20 to 88 years who performed a maximal treadmill exercise test at baseline in the Aerobics Center Longitudinal Study (Dallas, TX) during 1974 to 2003. Mortality was assessed over 29 years of follow-up (1974-2003). Two hundred eighty-three digestive system cancer deaths occurred during a mean 17 years of observation. Age-adjusted mortality rates per 10,000 person-years according to low, moderate, and high CRF groups were 6.8, 4.0, and 3.3 for digestive system cancer (P(trend) < 0.001). After adjustment for age, examination year, body mass index, smoking, drinking, family history of cancer, personal history of diabetes, hazard ratios (95% confidence intervals) for overall digestive cancer deaths for those in the middle and upper 40% of the distribution of CRF relative to those in the lowest 20% were 0.66 (0.49-0.88) and 0.56 (0.40-0.80), respectively. Being fit (the upper 80% of CRF) was associated with a lower risk of mortality from colon [0.61 (0.37-1.00)], colorectal [0.58 (0.37-0.92)], and liver cancer [0.28 (0.11-0.72)] compared with being unfit (the lowest 20% of CRF). These findings support a protective role of CRF against total digestive tract, colorectal, and liver cancer deaths in men.