The mechanism of adverse tissue reaction to implant derived cobalt and chromium is unknown. It is possible that only one of these metals, cobalt, plays critical role in the failure of MOM implant. Cobalt ions are known to stabilize hypoxia inducible factor (HIF) 1α, which is involved in inflammatory pathway involving upregulation of BNIP3, GLUT1, HO-1 and COX-2 genes. This study used human monocytic cell line U937 to test the cytotoxic and inflammatory response to cobalt and chromium in form of ions and nanoparticles (NP) at clinically relevant doses. MTT assay was used to assess cytotoxic potential of metals for up to 24 hours. Gene expression was studied using qPCR and protein expression using Western Blot technique. Inflammatory cytokine release was studied using ELISA assay. Cytotoxicity study showed similar toxicity cobalt NP throughout the range of concentration 5–100μg/ml. Stabilization of HIF1α protein was observed after stimulation with cobalt ions and NP. This resulted in upregulation of GLUT1, BNIP3, HO-1 and COX-2 genes. Stimulation caused increased release in TNFα and inhibition of IL-10. No significant release of IL-1β was observed. Stimulation with chromium ions or NP did not cause any changes in cell viability, stabilization of HIF or cytokine release profile. Chromium NP caused upregulation of COX-2 after 6 hours of exposure. These results indicate significant role of cobalt in the inflammatory process and its potential as the cause of failure of MOM implants.