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Current physical activity guidelines are based in part on studies of cardiorespiratory fitness, however, the effects of fitness may differ from activity. Analyses were undertaken to determine the dose-response relationships of fitness to incident hypertension, hypercholesterolemia, and diabetes independent of activity.Self-reported physician-diagnosed incident diabetes, hypercholesterolemia, and hypertension were compared to baseline running distance in 29,139 men and 11,985 women followed prospectively for 7.7 and 7.4 yr, respectively, and compared to cardiorespiratory fitness (m·s−1 10-km performance) in 85% of men and 76% of women.During follow up, 2342 men (8.53%) and 499 women (4.26%) became hypertensive, 3330 men (12.2%) and 599 women (5.14%) became hypercholesterolemic, and 197 men (0.68%) and 28 women (0.23%) became diabetic. Longer baseline distance predicted lower incident hypertension (men, P < 0.0001; women, P = 0.08), hypercholesterolemia (men and women, P < 0.0001), and diabetes (men, P < 0.001; women, P < 0.01) during follow up. The odds for hypercholesterolemia decreased significantly with each 16 km·wk−1 increment in distance through 64 km·wk−1 in men and 48 km·wk−1 in women. Higher baseline fitness predicted significantly lower odds for incident hypertension (men, P < 0.0001; women, P < 0.001), hypercholesterolemia (men, P < 0.0001; women, P < 0.01), and diabetes (men, P < 0.001; women, P < 0.01), independent of distance. Compared to the least fit men, the fittest men had 62% lower odds for becoming hypertensive, 67% lower odds for becoming hypercholesterolemic, and 86% lower odds for becoming diabetic. When adjusted for BMI, greater fitness predicted significantly lower odds for hypertension, hypercholesterolemia, and diabetes in men.Higher cardiorespiratory fitness reduces the odds for hypertension, hypercholesterolemia, and diabetes, independent of physical activity and is an important risk factor separate from physical activity.