The rat is commonly used to evaluate physiological responses of subcutaneous tissue to implanted devices. In vivo longevity of various devices and the biocompatibility of biomaterials depend on how adjacent tissue interacts. How closely the rat model predicts the human response has not been well characterized. The objective of this study was to compare rat and human subcutaneous foreign body responses by monitoring the biochemical environment at a polymer-tissue interface over eight days using microdialysis. Polyamide microdialysis probes were implanted subcutaneously in humans and rats (n=12). Daily microdialysis samples were analyzed for glucose, lactate, pyruvate, glycerol and urea. Blood glucose was also monitored. Analyte concentrations differed significantly between rats and humans at the implant-tissue interface. There were also qualitative differences in the eight-day trends. For example, over eight days, microdialysate glucose increased 2-4 fold in humans, but decreased in rats (p<0.001). This study reveals profound physiological differences at material-tissue interfaces in rats and humans and highlights the need for caution when extrapolating subcutaneous rat biocompatibility data to humans.