Metal ion toxicity is a major cause for concern in metal–metal hip replacements. A previous study in our laboratory demonstrated that Co²⁺ and Cr³⁺ induce macrophage apoptosis in vitro at 24h, with the implication of a caspase-3 pathway. The aim of the present study was to look at the effect of a prolonged incubation time on macrophage response with regards to TNF-α secretion and macrophage mortality, more specifically apoptosis. J774 macrophages were exposed for up to 48h to 0–10ppm Co²⁺ and 0–500ppm Cr³⁺. ELISA results demonstrated that Co²⁺ and Cr³⁺ induced a concentration- and time-dependent increase of TNF-α secretion, but a decrease at the highest concentrations of Cr³⁺ (350–500ppm). This decrease was most likely due to a high toxicity of Cr³⁺ at such concentrations. Higher levels of TNF-α were observed with Co²⁺ than Cr³⁺, demonstrating a higher stimulatory effect of this ion. Trypan blue and flow cytometry results demonstrated that both Co²⁺ and Cr³⁺ ions induce macrophage mortality in a dose- and time-dependent manner. The number of cells decreased when ion concentrations increased, especially at 48h. In parallel with the TNF-α results, Co²⁺ was more toxic than Cr³⁺ since the maximal effects were reached with lower concentrations (8–10ppm vs. 350–500ppm, respectively). DNA analysis demonstrated that both Co²⁺ and Cr³⁺ ions induce macrophage apoptosis, with a stronger signal at 24h than at 48h, suggesting the presence of more necrosis after 48h. PARP cleavage, another marker of apoptosis, was observed at both 24 and 48h, with a maximum intensity at 48h and with the highest concentrations of ions. In conclusion, this study demonstrates that both Co²⁺ and Cr³⁺ ions can induce the release of TNF-α and macrophage mortality in a dose- and time-dependent manner. More specifically, Co²⁺ and Cr³⁺ ions induced apoptosis after both 24 and 48h incubation, although DNA analysis suggested the presence of necrosis at 48h. The relative importance of apoptosis and necrosis in the induction of macrophage mortality by these metal ions remains to be investigated.