In this study we investigated the role of NO in Pb-induced yeast cell death. We found that the rate of cell death increased with increasing concentrations of Pb(NO₃)₂ and prolonged exposure to Pb(NO₃)₂. NO production also increased significantly during Pb-induced yeast cell death. An exogenous NO donor increased Pb toxicity to cells, while NO synthesis inhibitors and NO-specific scavengers alleviated Pb toxicity. To further investigate the mechanism of NO in Pb toxicity, we measured the Pb content and mRNA expression of metal ion transport gene SMF1 in yeast cells. Our results showed that endogenous NO may enhance SMF1 expression, thereby increasing Pb content in yeast cells. Meanwhile, we found that the intracellular ROS levels increased with the increase of intracellular Pb content in yeast cells. Conclusion: Pb can promote the increase of intracellular nitric oxide levels. NO may promote intracellular Pb transport by enhancing the expression of SMF1 in Pb-induced yeast cell death. Intracellular accumulation of Pb further promotes the increase of intracellular ROS levels, and then lead to yeast cell death by oxidative damage.