Increased resting heart rate (RHR) is a predictor of mortality. RHR is influenced by cardiorespiratory fitness (CRF). Little is known about the combined associations of RHR and CRF on cancer mortality. 50,108 men and women (mean age 43.8 years) were examined between 1974 and 2002 at the Cooper Clinic in Dallas, Texas. RHR was measured by electrocardiogram and categorized as <60, 60-69, 70-79, or ≥80 beats/minute. CRF was quantified by maximal treadmill test and dichotomized as unfit and fit corresponding to the lower 20% and the upper 80%, respectively, of the age- and sex-specific distribution of treadmill exercise duration. The National Death Index was used to ascertain vital status. Cox regression was used to compute HRs and 95% confidence intervals (CI) for cancer mortality across RHR categories. During a mean follow-up of 15.0 ± 8.6 years, 1,090 cancer deaths occurred. Compared with RHR <60 beats/minute, individuals with RHR ≥80 beats/minute had a 35% increased risk of overall cancer mortality (HR, 1.35; 95% CI, 1.06-1.71) after adjusting for confounders, including CRF. Compared with "fit and RHR <80 beats/minute", HRs (95% CI) for cancer mortality were 1.41 (1.20-1.66), 1.51 (1.11-2.04), and 1.78 (1.30-2.43) in "unfit and RHR <80," "fit and RHR ≥80," and "unfit and RHR ≥80 beats/minute," respectively. RHR ≥80 beats/minute is associated with an increased risk of overall cancer mortality. High CRF may help lower the risk of cancer mortality among those with high RHR. RHR along with CRF may provide informative data about an individual's cancer mortality risk.