Hydrogen sulfide (H S) exhibits promising protective effects in many (patho)physiological processes, as evidenced by recent reports using synthetic H S donors in different biological models. Herein, we report the design and evaluation of compounds denoted PeroxyTCM, which are the first class of reactive oxygen species (ROS)-triggered H S donors. These donors are engineered to release carbonyl sulfide (COS) upon activation, which is quickly hydrolyzed to H S by the ubiquitous enzyme carbonic anhydrase (CA). The donors are stable in aqueous solution and do not release H S until triggered by ROS, such as hydrogen peroxide (H O ), superoxide (O ), and peroxynitrite (ONOO ). We demonstrate ROS-triggered H S donation in live cells and also demonstrate that PeroxyTCM-1 provides protection against H O -induced oxidative damage, suggesting potential future applications of PeroxyTCM and similar scaffolds in H S-related therapies.