Factors controlling metabolic flexibility (MF), the ability of the body to switch from fat to carbohydrate oxidation in response to feeding or with insulin administration, are being actively investigated. We sought to determine the effects of race (African American vs Caucasian) and diabetes status (nondiabetic vs type 2 diabetes mellitus individuals) on MF to glucose in humans. Respiratory quotient (RQ) and macronutrient substrate utilization were evaluated by indirect calorimetry during baseline (fasting) and hyperinsulinemic-euglycemic clamp (insulin infusion of 120 mU·m⁻²·min⁻¹); ΔRQ (MF) = clamp RQ − fasting RQ. The study included 168 human subjects of different races (55 African Americans, 113 Caucasians), sex (73 men, 95 women), ages (18-73 years), body mass index (19.3-47.7 kg/m²), and diabetes status (89 nondiabetic, 79 type 2 diabetes mellitus subjects). Metabolic flexibility was negatively correlated (P < .01) with age (r = − 0.41), fasting RQ (r = −0.22), fasting glucose (r = −0.55), insulin (r = −0.40), and triglyceride (r = −0.44) concentrations; whereas a positive association was observed with insulin sensitivity (r = 0.69, P < .0001). Insulin sensitivity, fasting RQ, triglyceride concentrations, diabetes status, and race accounted for 71% of the variability in MF with insulin sensitivity being the main determinant factor (model R² = 0.48, P < .0001). After controlling for the significant predictors, MF was higher in African Americans vs Caucasians (mean ± SEM 0.080 ± 0.004 vs 0.069 ± 0.002, P = .008) and in nondiabetic vs type 2 diabetes mellitus subjects (P = .003). This study confirms that insulin sensitivity is the major contributor to MF in humans, but provides the novel findings that African Americans have significantly greater MF than Caucasians even after adjusting for insulin sensitivity and diabetes status.