Nitric oxide is emerging as one of the most studied molecules in many aspects of human physiology and pathophysiology. Because of the inflammatory nature of aseptic loosening of total hip replacement, it is likely that nitric oxide plays a major role in this condition as well. Nitric oxide is known to interact with cyclooxygenase enzymes that produce prostanoids. Nitric oxide can stimulate synthesis and activity of the inducible, proinflammatory isoform of the enzyme, namely, cyclooxygenase 2. Interactions between the cytokine inducible nitric oxide synthase and cyclooxygenase 2 pathways serve to regulate bone cell viability such that cyclooxygenase 2 activity can protect against nitric oxide mediated programmed cell death. In the pseudomembrane these two pathways are coactivated in CD68 positive macrophages, fibroblasts, lining cells, and in vascular smooth muscles. Particle generation from wear of the prosthesis has a significant role as an inducer of nitric oxide synthase and cyclooxygenase 2; macrophages laden with small size particles and positive for inducible nitric oxide synthase and cyclooxygenase 2 are a frequent finding. Nitric oxide readily reacts with superoxide to form peroxynitrite, which is a strong oxidant species. In pseudosynovial interface membrane, detection of nitrotyrosine provides evidence for the formation and activity of peroxynitrite. These findings show evidence that nitric oxide, superoxide, and peroxynitrite mediated cellular damage is part of the pathophysiology of aseptic loosening of joint implants. These new findings suggest that antiinflammatory compounds can be useful to treat early aseptic loosening of joint implants.