The hypothesis that unconjugated bilirubin and biliverdin are cytoprotective antioxidants has been examined for the first time in systems containing cells. In primary rat hepatocytes exposed to xanthine oxidase and hypoxanthine, bilirubin (0–60 μM) failed to prolong cell survival. In contrast, biliverdin (20–100 μM) markedly delayed hepatocyte necrosis in a concentration-dependent manner. When 0.3 mM of albumin was present, bilirubin (0–50 μM) became protective of hepatocytes, while biliverdin was less dramatically enhanced in its cytoprotective effect. In human erythrocytes exposed to peroxyl radicals, bilirubin and biliverdin inhibited 50% cell lysis at lower concentrations than Trolox and ascorbate, respectively. Albumin alone appeared less cytoprotective in red cells than in hepatocytes, but its presence enhanced the effects of both pigments on erythrocytes. Of probable physiologic relevance, bilirubin with albumin present or biliverdin alone protected hepatocytes substantially (and to a lesser extent red cells) at the normal blood levels of bilirubin (3.4–26 μM). Moreover, the fact that the pigments are cytoprotective at higher bilirubin levels (e.g., 50–100 μM) tempts the speculation that they may be circulating cytoprotectors of overlooked importance in jaundice.Key words: cytoprotection, biliverdin, bilirubin, albumin.