Exogenous H 2 S has proven to be a potent antioxidant, not only because of its direct effect on ROS scav- enging but also due to its capacity to activate the endogenous antioxidant defense system. Therefore, exogenous H 2 S could potentially influence the course of inflammation by reducing secondary altera- tions. The study aimed to determine the combined effect of NaHS and nimesulide on the development of oxidative-nitrosative stress in the myocardium of rats subjected to lipopolysaccharide-induced systemic inflammatory response. The experiments were performed on 30 Wistar rats. The animals were divided into 5 groups: control (received saline); LPS group, rats that were injected intraperitoneally with 0.4 μg/kg of bacterial LPS S. typhi (first week thrice a week, then 1 time a week for 30 days); group of rats treated with nimesulide and LPS, received same treatment as in LPS group but in last seven days of experiment additionally were administered orally 18.15 mg/kg of nimesulide; group with administration NaHS and LPS, rats received the same treatment as in LPS group, but in the last seven days of the experiment, were additionally administered intraperitoneally 5 mg/kg of NaHS; group with administration nimesulide, NaHS and LPS, rats received same treatment as in LPS group but in last seven days of experiment additionally were administered orally 18 mg/kg of nimesulide and intraperitoneally 5 mg/kg NaHS. In the rat blood, we studied C-reactive protein content, and in 10% rat myocardium homogenate, we studied parameters of oxidative stress, functioning of nitric oxide cycle and hydrogen sulfide content. Lipopolysaccharide loading of the body is accompanied by hyperproduction of active nitrogen forms and the development of oxidative damage to myocardial lipids and proteins, with a compensatory increase in the activity of antioxidant en- zymes. Simultaneous administration of nimesulide and NaHS during LPS-inflammation decreased cNOS activity by 1.22 times, nitrosothiols concentration by 3.41 times, peroxynitrite by 1.61 times, superoxide production by 4.85 times, and nitrites increased by 1.98 times, catalase activity by 2.31 times, superoxide dismutase by 3.75 times, malondialdehyde decreased by 3.47 times, sulfides by 2.98 times and oxidatively modified proteins by 2.43 times compared to the control. Thus, the use of nimesulide, the introduction of a hydrogen sulfide donor, and their combined use under conditions of lipopolysaccharide-induced systemic inflammation lead to a decrease in the excessive production of nitric oxide and its toxic metabolites in the myocardium of rats. At the same time, a synergistic effect of nimesulide and exogenous hydrogen sulfide is observed only in reducing the intensity of oxidative damage to lipid structures of the myocardium under conditions of lipopolysaccharide-induced systemic inflammatory response.