Purpose: The impact of lifestyle factors on cancer mortality in the U.S. population has not been thoroughly explored. We examined the combined effects of cardiorespiratory fitness, never smoking, and normal waist girth on total cancer mortality in men.Methods: We followed a total of 24,731 men ages 20–82 years who participated in the Aerobics Center Longitudinal Study. A low-risk profile was defined as never smoking, moderate or high fitness, and normal waist girth, and they were further categorized as having 0, 1, 2, or 3 combined low-risk factors.Results: Over an average of 14.5 years of follow-up, there were a total of 384 cancer deaths. After adjustment for age, examination year, and multiple risk factors, men who were physically fit, never smoked, and had a normal waist girth had a 62% lower risk of total cancer mortality (95% confidence interval [CI], 45%–73%) compared with men with no low-risk factors. Men with all 3 low-risk factors had a 12-year (95% CI, 8.6–14.6) longer life expectancy compared with men with no low-risk factors. Approximately 37% (95% CI, 17%–52%) of total cancer deaths might have been avoided if the men had maintained all 3 low-risk factors.Conclusions: Being physically fit, never smoking, and maintaining a normal waist girth is associated with lower risk of total cancer mortality in men.