Cell surface 'blebbing' is an early consequence of hypoxic and toxic injury to cells1-5. A rise in cytosolic free Ca2+ has been suggested as the stimulus for bleb formation3-5 and the final common pathway to irreversible cell injury6-9. Here, using digitized low-light video microscopy, we examine blebbing, cytosolic free Ca2+, mitochondrial membrane potential and loss of cell viability in individual cultured hepatocytes. Unexpectedly, we found that after 'chemical hypoxia' with cyanide and iodoacetate, cytosolic free Ca2+ does not change during bleb formation or before loss of cellular viability. Cell death was precipitated by a sudden breakdown of the plasma membrane permeability barrier, possibly caused by rupture of a cell surface bleb.