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Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator that is used as a treatment for persistent pulmonary hypertension in neonates (PPHN) with hypoxic respiratory failure. The generation of reactive oxygen and nitrogen species might induce oxidative/nitrosative damage to multiple organs. There is an increasing scientific and clinical interest in the determination of specific biomarkers to measure the degree of oxidative/nitrosative stress in non-invasively collected biofluids. A method for the simultaneous detection of a panel of oxidative and nitrosative stress-related biomarkers for quantifying damage to proteins and DNA/RNA in 20 μL of infant urine samples based on reversed-phase ultra-performance liquid chromatography coupled to tandem mass spectrometry operating in positive electrospray ionization mode (ESI + ) was optimized and validated. Infant urine samples from two different studies were analyzed: (i) term and preterm infants from a nutrition study (Nutrishield, N = 50) and (ii) infants with respiratory insufficiency, including infants with PPHN (N = 16) that required iNO treatment and a control group without treatment (N = 14). Eleven of 14 metabolites were detected in >50 % of infant urine samples, with ranges between 0.008 and 1400 μmol/g creatinine. When comparing across groups, differences in samples collected after iNO treatment in comparison to the rest of the groups were found for m-tyrosine (m-Tyr and m-Tyr/Phe) and ortho-tyrosine (o-Tyr and o-Tyr/Phe) (p-values <0.001, Wilcoxon rank-sum test). Positive linear relationships were found with NO exposure corrected by infant weight for m-Tyr, m-Tyr/Phe, o-Tyr, o-Tyr/Phe and 3-nitrotyrosine. Future studies will focus on the evaluation of the impact of iNO treatment on health and oxidative/nitrosative stress-related morbidities associated with prematurity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Julia Kuligowski reports financial support was provided by Carlos III Health Institute. Abel Albiach-Delgado reports financial support was provided by Carlos III Health Institute. Aljandro Pinilla-González reports financial support was provided by Carlos III Health Institute. Inmaculada Lara Cantón reports financial support was provided by Carlos III Health Institute. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)