The relationship between metabolic flexibility (MF) and components of metabolic disease has not been well-studied among African American (AA) females and may play a role in the higher incidence of chronic disease among them compared with Caucasian American (CA) females. This pilot study aimed to compare the metabolic response of AA and CA females after a high-fat meal. Eleven AA (25.6 (5.6) y, 27.2 (6.0) kg/m(2), 27.5 (9.7) % body fat) and twelve CA (26.5 (1.5) y, 25.7 (5.3) kg/m(2), 25.0 (7.4) % body fat) women free of cardiovascular and metabolic disease and underwent a high-fat meal challenge (55.9% fat). Lipid oxidation, insulin, glucose, and interleukin (IL)-8 were measured fasted, 2 and 4 h postprandial. AA females had a significantly lower increase in lipid oxidation from baseline to 2 h postprandial (p = 0.022), and trended lower at 4 h postprandial (p = 0.081) compared with CA females, indicating worse MF. No group differences in insulin, glucose or HOMA-IR were detected. IL-8 was significantly higher in AA females compared with CA females at 2 and 4 h postprandial (p = 0.016 and p = 0.015, respectively). These findings provide evidence of metabolic and inflammatory disparities among AA females compared with CA females that could serve as a predictor of chronic disease in individuals with a disproportionately higher risk of development.