Background: Because lifestyle-induced improvements in cardiovascular risk factors vary substantially across individuals with type 2 diabetes, we investigated the extent to which increases in fitness explain cardiovascular risk factor improvements independent of weight loss in a lifestyle intervention. Methods: We studied 1-year changes in Look AHEAD, a randomized trial comparing an intensive lifestyle intervention (ILI) to a diabetes support and education (DSE) control group in adults with type 2 diabetes. Assessments included weight, fitness, blood pressure (BP), glucose, HbA1c, and lipids.We evaluated the effects of changes in weight and fitness on changes in cardiovascular risk factors by study arm, using R2 from multiple linear regression. Results: Analyses included participants with fitness data at baseline and 1-year (n=4408; 41% male, 36% non-white; mean age 58.7 6.8 years). Weight change alone improved R2 for explaining changes in risk factors up to 8.2% in ILI and 1.7% in DSE. Fitness change alone improved R2 up to 3.9% in ILI and 0.8% in DSE. After adjusting for weight change, fitness was independently associated (p<0.05) with improvements in R2 for glucose (+0.7%), HbA1c (+1.1%), highdensity lipoprotein (HDL) cholesterol (+0.4%), and triglycerides (+0.2%) in ILI and diastolic BP (+0.3%), glucose (+0.3%), HbA1c (+0.4%), and triglycerides (+0.1%) in DSE. Taken together, weight and fitness changes explained from 0.1-9.3% of the variability in cardiovascular risk factor changes. Conclusion: Increased fitness explained statistically significant but small improvements in several cardiovascular risk factors beyond weight loss. Further research identifying other factors that explain cardiovascular risk factor change is needed. © 2012 The European Society of Cardiology.