Many vascular diseases are characterized by increased levels of reactive oxygen species (ROS) that destroy the biological activity of nitric oxide (NO) and limit cGMP formation. Herein, we investigated the cGMP-forming ability of HMR-1766 in cells exposed to oxidative stress. Pre-treatment of smooth muscle cells with H₂O₂ reduced cGMP production stimulated by sodium nitroprusside (SNP) or BAY 41-2272. However, pre-treatment with H2O2 significantly increased the HMR-1766 responses. Similar results were obtained with SIN-1, menadione and rotenone. In addition, HMR-1766 was more effective in stimulating heme-free sGC as compared to the wild-type enzyme. Interestingly, in cells expressing heme-free sGC H₂O₂ inhibited, instead of potentiating the HMR-1766 responses, suggesting that the ROS-induced enhancement of cGMP formation was heme-dependent. Moreover, using truncated forms of sGC, we observed that the N-terminus of the 1 is required for the action of HMR-1766. Finally to study tolerance development to HMR-1766, cells were pretreated with this sGC activator and re-exposed to HMR-1766 or SNP. Results from these experiments demonstrated lack of tolerance development to HMR-1766, as well as lack of cross-tolerance with SNP. We conclude that HMR-1766 is an improved sGC activator as it has the ability to activate oxidized/heme-free sGC and is resistant to the development of tolerance; these observations make HMR-1766 a promising agent for treating diseases associated with increased vascular tone combined with enhanced ROS production.