Nitric oxide (NO) is an effector molecule associated with inflammation, immune function, bone metabolism, and the induction of apoptosis. This study examined the role of NO, peroxynitrite (ONOO(-)), and apoptosis in cases of revision total hip replacements (THRs). We hypothesized that apoptosis and excess production of NO contribute to the inflammatory reaction to orthopedic biomaterial wear debris that is associated with loosening and osteolysis. Periprosthetic membranous specimens were collected from revised cemented acetabular components with simple loosening and ballooning osteolysis. Synovial samples from patients undergoing primary THR were used as controls. The presence of macrophages (CD68(+)) and levels of inducible nitric oxide synthase (INOS), endothelial nitric oxide synthase (EcNOS), ONOO(-) (Nitro, assayed by the amount of nitrated tyrosine residues), and apoptosis (TUNEL staining) were examined using immunohistochemistry. Increased expression for INOS, EcNOS, and ONOO(-) in both the loose/osteolytic and the loose/non-osteolytic groups was observed when compared to the synovium group. There were no significant differences between the loose/osteolytic group and loose/non-osteolytic group for these biologic markers. TUNEL staining showed a significant increase in apoptosis in the loose/osteolytic group compared to the loose/non-osteolytic group and synovial tissues. These findings suggest that NO and NO-derived molecules, such as ONOO(-), may be involved in sustaining the foreign-body reaction to wear debris. NO and ONOO(-) may prove to be useful markers of prosthetic loosening whereas apoptosis may be a marker distinguishing ballooning from simple osteolysis.