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Bilirubin (BR), the final product of heme catabolism, plays a crucial role in the defense against reactive oxygen species in various cell types. In this study, we addressed the hypothesis that BR can act as a physiological scavenger of nitric oxide (NO), a gaseous mediator involved in many cellular functions and able to trigger the formation of reactive nitrogen species with pro-oxidant activity. We found that S-nitrosocysteine (SNOC) and S-nitrosoglutathione (GSNO), which have a half-life of 0.52±0.07 hr and 38±5 hr and release NO at a constant rate of 1.42±0.2 hr−1 and 0.018±0.002 hr−1, respectively, were able to decrease BR half-life in a concentration-dependent manner under physiological conditions. This effect appears to be dependent on NO formation as l-cysteine and GSH did not affect BR consumption and nitrite was four to five times less efficient than SNOC in reducing BR half-life. Oxyhemoglobin, a well-known scavenger of NO, protected BR from SNOC-mediated degradation. In addition, the reaction between SNOC/GSNO and BR modified the absorption spectrum of the bile pigment showing a gradual increase in the absorbance at 316 nm. This change in the BR spectrum indicates that the bile pigment could be a target for N-nitrosation reactions, since it resembles the modifications occurred when other molecules such as di-peptides and uric acid are nitrosated. Taken together, these data suggest that BR should not be considered only as an endogenous antioxidant but also as a molecule with the potential ability to counteract intracellular nitrosative stress reactions.