Aims/hypothesis: Distinguishable sex differences exist in fat mass and muscle mass. High fat mass and low muscle mass are independently associated with cardiovascular disease (CVD) risk factors in patients with type 2 diabetes; however, it is unknown if the association between fat mass and CVD risk is modified by muscle mass, or vice versa. The primary aim of this study was to examine the sex-specific interplay between fat mass and muscle mass on CVD risk factors in type 2 diabetes. The secondary aim was to explore whether baseline fat mass and muscle mass influenced lifestyle-induced changes in CVD risk factors. Methods: A secondary analysis was conducted on data collected in the Look AHEAD trial. Dual-energy X-ray absorptiometry (DXA) measures were used to compute fat mass index (FMI) and appendicular muscle mass index (ASMI), and participants were separated in to high-fat mass (i.e., 50-100 FMI deciles) vs. low-fat mass (i.e., 0-49.99 FMI deciles) and high-muscle mass (50-100 ASMI deciles) vs. low-muscle mass (0-49.99 ASMI deciles). A two-way analysis of covariance (ANCOVA: high-FMI vs. low-FMI by high-ASMI vs. low-ASMI) was performed on CVD risk factors (i.e., hemoglobin A1C [A1C]; fasting blood glucose; high-density lipoprotein cholesterol [HDL-C]; low-density lipoprotein cholesterol [LDL-C]; triglycerides; systolic and diastolic blood pressure; cardiorespiratory fitness, depression and health related-quality of life [QoL]) for females and males separately at baseline and following intensive lifestyle intervention (ILI), with a primary focus on the fat mass by muscle mass interaction effects. Results: Data from 1,369 participants (62.7% females) who completed baseline DXA were analyzed. In females, there was a fat mass by muscle mass interaction effect on A1C (p=0.016). Post-hoc analysis showed that, in the low-FMI group, A1C was significantly higher in low-ASMI when compared to high-ASMI (60.3±14.1 vs. 55.5±13.5 mmol/mol [7.7±1.3 vs. 7.2±1.2%], p=0.023). In the high-FMI group, there was no difference between high-ASMI and low-ASMI (56.4±12.5 vs. 56.5±12.8 mmol/mol [7.3±1.1 vs. 7.3±1.2%] p=0.610). In males, only high-FMI was associated with higher A1C when compared to low-FMI (57.1±14.4 vs. 54.2±12.0 mmol/mol [7.4±1.3 vs. 7.1±1.1%], p=0.008). Following ILI, there was a significant fat mass by muscle mass interaction effects on changes in mental component of QoL in males. Post hoc analyses showed a significantly greater increase in mental QoL scores in high-ASMI vs. low-ASMI in high-FMI (5.2±9.4 vs. 1.2±9.5 points, p=0.016), whereas the mental QoL scores increased more in low-ASMI vs. high-ASMI in low-FMI (3.5±6.5 vs. 0.1±6.6 points, p=0.042). Conclusion: Considering that A1C predicts future CVD, strategies to lower A1C may be especially important in females with low fat and low muscle mass living with type 2 diabetes. Our results highlight the complicated and sex-specific contribution of fat mass and muscle mass to CVD risk factors.