We have shown that abnormal exercise test responses (ETR), denned as abnormal electrocardiogram results, abnormal blood pressure response and exercise-induced chest pain, are directly associated with death from coronary heart disease (CHD) in initially asymptomatic men. Cardiorespiratory fitness (CRF) is also inversely associated with CHD risk. The enhancement in CHD risk prediction when considering both maximal ETR and CRF is less understood. PURPOSE: We examined the associations between CRF and ETR and CHD mortality in 42,329 men (mean±SD, age 43±10 years) who completed a preventive medical examination at the Cooper Clinic, Dallas, TX between 1970 and 2001. METHODS: At baseline, all men were asymptomatic and free of physician diagnosed myocardial infarction or stroke, and had clinical measures including resting blood pressure, fasting blood chemistry, and a symptom-limited maximal treadmill exercise test. CRF categories were based on age-specific distributions of exercise duration denned as low (lowest 20%) and moderate-high CRF (highest 80%). An abnormal ETR was denned above. An equivocal ETR was denned as an equivocal exercise electrocardiogram. Framingham risk scores (FRS) were computed and men were grouped in categories of <10% and >10%. Mortality follow-up was through 2003 primarily using the National Death Index. RESULTS: During an average follow-up of 17.4±7.9 years, 632 (1.5%) CHD deaths occurred. Approximately 6% of men had an equivocal ETR and 6% had an abnormal ETR. Age-adjusted CHD mortality rates per 10,000 person-years of exposure across low and moderate-high CRF groups were 11.4 and 4.9 for men with normal ETR, 31.3 and 13.5 for men with equivocal ETR and 59.6 and 27.4 for men with abnormal ETR. Based on a Cox regression model that included baseline exam year, age, CRF, ETR, FRS, all were independently associated with CHD mortality. Hazard ratios (95% CI) were 0.50 (0.42–0.59) for moderate-high CRF; 1.5 (1.2–2.0) for equivocal ETR, 2.4 (2.0–3.0) for abnormal ETR; 2.0 (1.6–2.4) for FRS ≥10%. Comparison of likelihood ratios indicated enhanced CHD risk prediction based on a model that included both CRF and ETR compared with either CRF or ETR alone. When grouped on ETR categories of normal, equivocal, and abnormal, hazard ratios (95% CI) for CHD mortality in men with moderate-high CRF were 0.48 (0.39–0.59), 0.48 (0.29–0.77) and 0.55 (0.39–0.76), respectively. CONCLUSION: In asymptomatic men without known CHD, CRF appears to enhance CHD risk prediction based on ETR alone. These findings indicate that functional and hemodynamic responses from maximal exercise testing can be valuable in assessing individuals seen in preventive medical settings.