The current study determined (I) the environment where oxidation in a series of retrieved, HXL UHMWPE tibial inserts occurred (in vivo or postexplant); and (II) the effect of fabrication variables (irradiation source, irradiation dose) and thermal processing after irradiation (annealing or remelting) on oxidation resistance. Hypotheses examined are (1) HXL UHMWPE tibial inserts have potential to oxidize in vivo, and (2) annealed HXL UHMWPE oxidizes at a higher rate in vivo than remelted HXL UHMWPE. Highly crosslinked UHMWPE tibial inserts (87), received by an IRB-approved retrieval laboratory from 20 surgeons at 10 institutions across the U.S., were analyzed from 2005 to 2011. Fourier transform infrared spectroscopy was used to determine oxidation and trans-vinylene index for each retrieved insert. Measured oxidation that was maximum subsurface was found in 56% of all HXL tibial inserts. This maximum oxidation correlated significantly with in vivo time, trans-vinylene index, and thermal processing after irradiation. Articular oxidation rate correlated with crosslinking irradiation dose and thermal processing after irradiation. Retrieved below-melt annealed tibial inserts had significantly higher articular oxidation rates than remelted tibial inserts (p < 0.001). Articular oxidation rates correlated positively with cross-linking irradiation dose and postirradiation thermal processing. Edge oxidation correlated with postirradiation thermal processing. Oxidation of HXL UHMWPE may have clinical implications for tibial inserts, since loss of UHMWPE toughness resulting from oxidation has led to fatigue damage in gamma-sterilized tibial inserts. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 101B: 441–448, 2013.