Lidocaine-induced apoptosis is abolished by a blockade of the mitochondrial pathway. Wild-type (wt), B-cell lymphoma-2 protein–overexpressing (Bcl-2), or caspase 9–deficient (casp-9⁻) cells were treated for 12 h with staurosporine (STS) or lidocaine in concentrations indicated. Early apoptosis was measured by flow cytometric staining with annexin-V to detect phosphatidylserine exposure. Counterstaining with propidium iodide (PI) was used to detect dead cells undergoing primary or secondary necrosis. Inhibition of the mitochondrial pathway by Bcl-2 overexpression or caspase-9 deficiency reduced the fraction of early apoptotic (annexin-V–positive, PI-negative) cells after treatment with 3 and 6 mm lidocaine and 1.25 μm STS. The fraction of cells undergoing a late phase of cell death (annexin-V–positive and PI-positive cells) was also significantly reduced (P< 0.05). Inhibition of the mitochondrial pathway, however, did not prevent cell death induced by 10 mm lidocaine, which was largely necrotic and observed in more than 90% of the cells. *P< 0.05.Error barsindicate SD.