Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, defined by motor neuron loss, muscle paralysis, and death. ALS individuals often present alterations in cardiovascular function that may evolve into heart failure and death. Mitochondrial dysfunction and oxidative stress are key players in ALS pathophysiology. Thus, improving mitochondrial function and/or antioxidant capacity constitute promising therapeutic strategies to delay ALS progression. We hypothesized that mitochondria-targeted antioxidant AntiOxCIN4 can reduce cardiac oxidative/nitrosative stress in SOD1G93A ALS mice.Early adult SOD1G93A mice were treated with AntiOxCIN4 (0.1 mg/Kg/day), for 2 months. We used cardiac homogenates, and colorimetry/fluorimetry-based methods to assess its role in oxidative/nitrosative stress markers, and in activities of the antioxidant enzymes superoxide dismutase (total SOD and SOD-2), glutathione peroxidase and reductase (GPx and GRed).We observed that AntiOxCIN4 increased the activities of total SOD, SOD-2, GPx, and GRed in ALS mouse hearts (P=0.05, P=0.03, P=0.0002, P=0.008), while slightly decreasing their cardiac nitrites levels (39%).In sum, AntiOxCIN4 treatment may counteract cardiac oxidative/nitrosative stress in ALS. Further research is needed to elucidate whether this protection delays ALS-associated cardiac impairment.Funding: ERDF: Centro2020 Operational Programme (POCI-01-0145-FEDER-029391 (Mito4ALS)) and COMPETE 2020; by Portuguese FCT (POCI-01-0145-FEDER-029391, PTDC/MED-FAR/29391/2017, UIDB/04539/2020, UIDP/04539/2020, LA/P/0058/2020, LA/P/0056/2020 (IMS), UIDB/00081/2020 (CIQUP)); by European Social Fund: 2021.04707.BD & Mito4ALS-PTDC/MED-FAR/29391/2017 (DM), DL57/2016 (FC), PT-OPENSCREEN-NORTE-01-0145-FEDER-085468 (SB), ERASMUS+ Student Mobility Grant (KM), SFRH/BD/5539/2020 (LFG), FCT Contract 2020.01560.CEECIND (JT), DOI: 10.54499/DL57/2016/CP1448/CT0006 & EU HORIZON-CSA-WIDERA-2022-ACCESS-04 Excellence Hubs/CHAngeing/II0347.01 (AID). PO and FB are founders of the spin-off company MitoTAG; FS is a current employer of MitoTAG.