In septic shock, systemic vasodilation and myocardial depression contribute to the systemic hypotension observed. Both components can be attributed to the effects of mediators that are released as part of the inflammatory response. We previously found that lysozyme (Lzm-S), released from leukocytes, contributed to the myocardial depression that develops in a canine model of septic shock. Lzm-S binds to the endocardial endothelium resulting in the production of nitric oxide (NO) that in turn activates the myocardial guanylate cyclase (sGC) pathway. In the present study, we determined whether Lzm-S might also play a role in the systemic vasodilation that occurs in septic shock. Methods and Results. In a phenylephrine contracted canine carotid artery ring preparation, we found that both canine and human Lzm-S, at concentrations similar to those found in sepsis, produced vasorelaxation. This decrease in force could not be prevented by inhibitors of nitric oxide synthase, prostaglandin synthesis, or potassium channel inhibitors and was not dependent on the presence of the vascular endothelium. However, inhibitors of the sGC pathway prevented Lzm-S’s vasodilatory activity. In addition, Aspergillus niger catalase that would breakdown hydrogen peroxide (H₂O₂) as well as hydroxyl radical scavengers that included hydroquinone and mannitol prevented Lzm-S’s effect. Electrochemical sensors corroborated that Lzm-S caused H₂O₂ release from the carotid artery preparation. Conclusions. These results support the notion that when Lzm-S interacts with the arterial vasculature, this interaction results in the formation of H₂O₂ that in turn activates the sGC pathway to cause relaxation. Lzm-S may contribute to the vasodilation that occurs in septic shock.