The aim of this study is to investigate in vitro release and cell response to wear particles of ultrahigh molecular weight polyethylene loaded with alendronate sodium (UHMWPE-ALN), a potent bone resorption inhibitor. Wear particles of UHMWPE-ALN with different ALN contents (0.5 wt % or 1.0 wt %) and size ranges (<45 μm or 45–75 μm) were cocultured with macrophages (RAW264.7) and osteoblasts (MC3T3-E1), respectively. The in vitro ALN release was divided into three stages: an initial burst release, subsequent rapid release, and final slow release. The particle size and ALN content of UHMWPE-ALN wear particles affected the in vitro release mainly during initial burst and rapid release. Compared with the control cells, UHMWPE-ALN wear particles stimulated a significant elevation of tumor necrosis factor-alpha (TNF-α) release from macrophages but had no obvious effect on interleukin-6 release. However, this stimulation of TNF-α release could be reduced by ALN released from UHMWPE-ALN wear particles. The wear particle size had stronger effect of on the macrophages compared with the ALN concentration. After coculture with UHMWPE-ALN wear particles, osteoblast proliferation and alkaline phosphatase activities increased moderately with the increase in particle sizes and ALN concentrations. These results suggest that incorporation of ALN in UHMWPE-ALN may be an effective approach to prevent or reduce particles-induced osteolysis. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.