The purpose of this study was to examine the relationship between metabolic adaptive response to 5 days of high SFA feeding, independent of positive energy balance, and diet-induced agonism of pro-inflammatory pathways. A secondary aim was to determine if the metabolic adaptive response in skeletal muscle to a single, high fat meal was altered by 5 days of high saturated fat feeding. Twelve college-age, non-obese males were studied and skeletal muscle samples were obtained prior to and concluding the consumption of a high SFA diet. In a subset of volunteers (N=6), we fed participants a high fat meal after the initial skeletal muscle biopsy and measured changes in postprandial endotoxin concentrations for four hours following the meal challenge. A second biopsy was obtained four hours after the meal challenge. Skeletal muscle samples were used to measure fatty acid oxidation, glucose oxidation, oxidative enzyme activities, mRNA expression of metabolic targets, and phosphorylation and total content of inflammatory proteins. In response to five days of high SFA feeding, skeletal muscle glucose and complete palmitate oxidation were significantly reduced as was the ratio of complete to incomplete fatty acid oxidation. Five days of high SFA feeding also attenuated the meal challenge-induced up-regulation of oxidative genes while augmenting postprandial increases in plasma endotoxin concentrations. To assess the relationship between metabolic adaptability and diet-induced inflammatory response we categorized volunteers by the diet induced percent change in fatty acid oxidation. Volunteers who were the least capable to adapt to high SFA feeding displayed the most robust increases in phosphorylation of inflammatory proteins. Lastly, we measured the correlation between the meal challenge associated percent change in oxidative and inflammatory markers in samples obtained prior to and following five days of high SFA feeding. We observed positive associations between the percent change in oxidative and inflammatory markers in samples obtained prior to the high SFA diet that were not observed following five days of high SFA feeding. These findings suggest that diet induced inflammatory response is involved in the regulation of adaptive response to high SFA feeding and that this relationship becomes dysregulated with chronic high SFA intake.