This study aimed to investigate the effects of the HMG-CoA reductase inhibitor simvastatin on ultra-high molecular weight polyethylene (UHMWPE) particle-induced osteolysis. The murine calvarial osteolysis model was used in 21 C57BL/J6 mice randomized to three groups. Group I underwent sham surgery only, group II received UHMWPE particles, and group III, particles and simvastatin treatment. After two weeks, calvaria were processed for histomorphometry. Bone resorption was measured as resorption within the midline suture using Giemsa staining. Osteoclast numbers were determined per high-power field using TRAP-staining. Statistical analysis was performed using one-way ANOVA and Student's t-test. Bone resorption in midline suture was 0.094+/-0.007 mm(2) in sham controls (group I), 0.25+/-0.025 mm(2) after particle implantation without further intervention (group II), and 0.131+/-0.02 mm(2) with particle implantation and additional simvastatin treatment (group III) (p=0.00003). Osteoclast numbers were 15.3+/-3.6 in group I, 48.7+/-7.1 in group II and 6.2+/-3.1 in group III (p=0.00002). In conclusion, simvastatin treatment markedly decreased UHMWPE particle-induced osteolysis in a murine calvarial model. This finding suggests that simvastatin may have a role for noninvasive prevention and treatment of wear debris-mediated periprosthetic osteolysis after total joint arthroplasty.