The replacement of a native hip joint by a metal‐on‐metal prosthesis may induce deleterious inflammatory side effects that are associated with the release of wear particles and metal ions. These events are referred to the adverse reaction to metal debris (ARMD) and the adverse local tissue reaction (ALTR). While wear particles seem involved in ARMD, the role of metal ions in ALTR and their impact on myoblasts, located in the prosthesis vicinity, has not been fully identified. To clarify this issue we investigated, using an in vitro culture system, the effect of cobalt and/or chromium ions (Co2+ and/or Cr3+) on human myoblast proliferation, cellular differentiation, and inflammatory marker expression. Freshly isolated human myoblasts were cultured in media supplemented with graded concentrations of Co2+ and/or Cr3+. Co2+ induced a concentration‐dependent decrease of both myoblast viability and myogenic differentiation while Cr3+ did not. Co2+ or Co2+/Cr3+ also induced the upregulation of ICAM‐1, whereas HLA‐DR expression was unaffected. Moreover, allogenic monocytes induced the synergistic increase of Co2+‐induced ICAM‐1 expression. We also found that Co2+ stabilized HIF‐1α and increased TLR4, tumor necrosis factor‐alpha (TNF‐α), and interleukin 1β (IL‐1β) expression in a dose and time‐dependent manner in human myoblasts. This study showed that Co2+, but not Cr3+, was toxic toward myoblasts and induced, in the surviving cells, expression of inflammatory markers such as ICAM‐1, TLR4, TNF‐α, and IL‐1β. This suggests that Co2+, most efficiently in the presence of monocytes, may be a key inducer of ALTR, which may, if severe and long‐lasting, eventually result in prosthesis loosening.