Introduction Objective estimates, based onwaist-wornaccelerometers, indicate that adults spend over half their day (55%) in sedentary behaviors. Our study examined the association between sitting time and cardiometabolic risk factors after adjustment for cardiorespiratory fitness (CRF). Methods A cross-sectional analysis was conducted with 4,486 men and 1,845 women who reported daily estimated sitting time, had measures for adiposity, blood lipids, glucose, and blood pressure, and underwent maximal stress testing. We used a modeling strategy using logistic regression analysis to assess CRF as a potential effect modifier and to control for potential confounding effects of CRF. Results Men who sat almost all of the time (about 100%) were more likely to be obese whether defined by waist girth (OR, 2.61; 95% CI, 1.25-5.47) or percentage of body fat (OR, 3.33; 95% CI, 1.35-8.20) than were men who sat almost none of the time (about 0%). Sitting time was not significantly associated with other cardiometabolic risk factors after adjustment for CRF level. For women, no significant associations between sitting time and cardiometabolic risk factors were observed after adjustment for CRF and other covariates. Conclusion As health professionals struggle to find ways to combat obesity and its health effects, reducing sitting time can be an initial step in a total physical activity plan that includes strategies to reduce sedentary time through increases in physical activity among men. In addition, further research is needed to elucidate the relationships between sitting time and CRF for women as well as the underlying mechanisms involved in these relationships.