Background: There is little research on the association of lifestyle exercise, such as active commuting (walking or biking to work), with obesity, fitness, and cardiovascular disease (CVD) risk factors. Methods: This cross-sectional study included 2364 participants enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study who worked outside the home during year 20 of the study (2005-2006). Associations between walking or biking to work (self-reported time, distance, and mode of commuting) with body weight (measured height and weight); obesity (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, ≥30); fitness (symptom-limited exercise stress testing); objective moderate-vigorous physical activity (accelerometry); CVD risk factors (blood pressure [oscillometric systolic and diastolic]); and serum measures (fasting measures of lipid, glucose, and insulin levels) were separately assessed by sex-stratified multivariable linear (or logistic) regression modeling. Results: A total of 16.7% of participants used any means of active commuting to work. Controlling for age, race, income, education, smoking, examination center, and physical activity index excluding walking, men with any active commuting (vs none) had reduced likelihood of obesity (odds ratio [OR], 0.50; 95% confidence interval [CI], 0.33-0.76), reduced CVD risk: ratio of geometric mean triglyceride levels (trigactive)/(trignonactive) = 0.88 (95% CI, 0.80 to 0.98); ratio of geometric mean fasting insulin (FIactive)/(FI nonactive) = 0.86 (95% CI, 0.78 to 0.93); difference in mean diastolic blood pressure (millimeters of mercury) (DBPactive) - (DBPnonactive) = -1.67 (95% CI, -3.20 to -0.15); and higher fitness: mean difference in treadmill test duration (in seconds) in men (TT active) -(TTnonactive) = 50.0 (95% CI, 31.45 to 68.59) and women (TTactive) - (TTnonactive) = 28.77 (95% CI, 11.61 to 45.92). Conclusions: Active commuting was positively associated with fitness in men and women and inversely associated with BMI, obesity, triglyceride levels, blood pressure, and insulin level in men. Active commuting should be investigated as a modality for maintaining or improving health.