Previous in vitro studies have shown that trivalent chromium ions (Cr3+) can induce cell death and the release of pro-inflammatory cytokines. In addition, chemokines such as MCP-1 and MIP-1α have been observed in the presence of implant wear particles. Therapeutic approaches to minimize the inflammatory response to metal ions leading to periprosthetic osteolysis and other adverse tissue reactions could help mitigate some of the concerns associated with metal ions from hip replacements. Therefore, the objective of this study was to analyze the effects of Cr3+ on macrophage mortality and morphology, as well as on the release of TNF-α, MCP-1, MIP-1α, MIP-1β, and RANTES, with and without simvastatin. J774A.1 macrophages were exposed to 50–500 ppm Cr3+ with and without 5 or 10 μM simvastatin for 24 h, in rotation. Mortality results showed that Cr3+ induced macrophage mortality in a dose-dependent manner. In addition, simvastatin at 10 μM effectively prevented Cr3+-induced vacuolization and cell swelling. Results also showed that while high concentrations of Cr3+ (particularly 500 ppm) may be too toxic to stimulate TNF-α and CC chemokine release, lower concentrations of Cr3+ are capable of inducing TNF-α and selective CC chemokine release, with a predominance of MIP-1α (up to 100% increase). Release of MCP-1 and RANTES were increased with up to 150 ppm Cr3+, but to a lower extent. The effects of simvastatin were dose-dependent, except for TNF-α and reduced the release of TNF-α as well as that of all chemokines at all Cr3+ concentrations analyzed, thereby demonstrating the potential of simvastatin to reduce metal ion-induced inflammatory response leading to periprosthetic osteolysis and other adverse tissue reactions.