Introduction. Adverse local tissue reactions (ALTR) can result in devastating soft tissue and osseous destruction, while potentially increasing the risk of concomitant periprosthetic joint infection (PJI). The aims of this study were to evaluate cobalt (Co) and chromium (Cr) levels generated in simulators from metal-on-polyethylene (MoP) and ceramic-on-polyethylene (CoP) constructs, and determine their impact on native tissues and PJI risk through evaluation of human adipose-derived mesenchymal stem cells (AMSCs) and Staphylococcus epidermidis isolates. Methods. Ten hip simulator constructs were assembled with 36-mm high-offset femoral heads, highly cross-linked polyethylene liners, and titanium stems. Five constructs used CoCr femoral heads and five used ceramic. Constructs were submerged in bovine serum (BS) and run for 1,000,000 cycles. Samples of BS were collected and evaluated for CoCr concentration. Various concentrations of CoCr were chosen for further assessment of cytotoxicity and growth impact on AMSCs and S. epidermidis and compared to inert SiO2. Results. After 1,000,000 cycles, mean MoP and CoP Co concentration was 2264 ng/mL and 0.6 ng/mL, respectively (p<0.001). Mean MoP and CoP Cr concentration was 217 ng/mL and 4.3 ng/mL, respectively (p<0.001). Mean MoP Co:Cr ratio was 10. Co nanoparticles were significantly more toxic to human AMSCs than control SiO2 in a dose-response manner (p<0.001). S. epidermidis growth was not significantly impacted by Co concentrations derived from the simulators. Conclusions. MoP constructs built in ideal conditions generated substantial CoCr debris, highlighting a baseline risk with these implants that may be exacerbated by host factors or imperfect surgical technique. Evaluation of impact on AMSCs suggests that debris levels produced under ideal conditions can be cytotoxic. Additionally, these concentrations did not potentiate or inhibit S. epidermidis growth, suggesting elevated PJI rates with ALTR may be related to other factors potentially associated with tissue necrosis. For any tables or figures, please contact the authors directly