Context: Low cardiorespiratory fitness is an established risk factor for cardiovascular and total mortality; however, mechanisms responsible for these associations are uncertain. Objective: To test whether low fitness, estimated by short duration on a maximal treadmill test, predicted the development of cardiovascular disease risk factors and whether improving fitness (increase in treadmill test duration between examinations) was associated with risk reduction. Design, Setting, and Participants: Population-based longitudinal cohort study of men and women 18 to 30 years of age in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants who completed the treadmill examination according to the Balke protocol at baseline were followed up from 1985-1986 to 2000-2001. A subset of participants (n=2478) repeated the exercise test in 1992-1993. Main Outcome Measures: Incident type 2 diabetes, hypertension, the metabolic syndrome (defined according to National Cholesterol Education Program Adult Treatment Panel III), and hypercholesterolemia (low-density lipoprotein cholesterol ≥160 mg/dL [4.14 mmol/L]). Results: During the 15-year study period, the rates of incident diabetes, hypertension, the metabolic syndrome, and hypercholesterolemia were 2.8, 13.0, 10.2, and 11.7 per 1000 person-years, respectively. After adjustment for age, race, sex, smoking, and family history of diabetes, hypertension, or premature myocardial infarction, participants with low fitness (<20th percentile) were 3- to 6-fold more likely to develop diabetes, hypertension, and the metabolic syndrome than participants with high fitness (≥60th percentile), all P<.001. Adjusting for baseline body mass index diminished the strength of these associations to 2-fold (all P<.001). In contrast, the association between low fitness and hypercholesterolemia was modest (hazard ratio [HR], 1. 4; 95% confidence interval [Cl], 1.1-1.7; P=.02) and attenuated to marginal significance after body mass index adjustment (P=.13). Improved fitness over 7 years was associated with a reduced risk of developing diabetes (HR, 0.4; 95% Cl, 0.2-1.0; P=.04) and the metabolic syndrome (HR, 0.5; 95% Cl, 0.3-0.7; P<.001), but the strength and significance of these associations was reduced after accounting for changes in weight. Conclusions: Poor fitness in young adults is associated with the development of cardiovascular disease risk factors. These associations involve obesity and may be modified by improving fitness.