Wear of ultra-high molecular weight polyethylene (UHMWPE) continues to be a major obstacle limiting the longevity of total joint replacements. Efforts to solve the wear problem in UHMWPE have resulted in numerous studies dealing with the microstructure, morphology, and mechanical properties of this polymer. However, the fundamental wear mechanisms at different material length scales in total joint replacements remain elusive. Consequently, a systematic investigation of the initial stage of the wear process was performed in this study in order to obtain insight into the origins of wear in UHMWPE at submicrometer scales. Sliding experiments were performed with both unmodified and crosslinked (by gamma radiation treatment) UHMWPE subjected to reciprocating sliding against Co-Cr alloy in a bath of bovine serum under ranges of mean contact pressure and sliding speed typical of knee joints. Nanoindentation and optical, scanning electron, and transmission electron microscopy were used to examine the effect of crosslinking on the nanomechanical properties, dominant wear mechanisms, and microstructure of UHMWPE. The fundamental wear micromechanisms of unmodified and crosslinked UHMWPE are interpreted in the context of coefficient of friction, wear factor, creep, adhesion force, and microstructure results.