Objective.To examine differences in genes involved in fat metabolism, energy homeostasis, adipogenesis, and inflammation between endstage and early-stage knee osteoarthritis (OA) infrapatellar fat pads (IFP).Methods.Twenty-nine endstage and 5 early-stage primary OA IFP were harvested at knee surgery. Total RNA was extracted, labeled, and hybridized to whole-genome expression arrays. Unsupervised analysis of all samples using principal components analysis or 2-way hierarchical clustering showed groupings based on tissue source and disease. Statistical testing identified sets of genes that displayed differences between the 2 fat types. Western blot analysis was performed for protein expression of an identified gene of interest.Results.The 29 IFP demonstrated an elevation in the expression of adipokines such as adiponectin and leptin. A statistically significant increased expression was seen for genes of adipogenesis, such as peroxisome proliferator-activated receptor-γ (PPAR-γ), diacylglycerol acyltransferase 2 (DGAT2), cluster of differentiation (CD36), and thyroid hormone responsive spot (THRSP) in the severe OA fat pads as compared to the controls. A subset of 5 patients in the endstage OA group were consistently similar in gene expression to early OA tissue. Protein expression of PPAR-γ2 was 5.4-fold and PPAR-γ1 was 1.4-fold greater in endstage versus early OA tissue.Conclusion.Endstage OA fat pads demonstrated a significant upregulation of genes for fat metabolism and energy homeostasis and a mixed result for inflammatory cytokines.