Several reports have suggested a reduction in the lung level of Dipalmitoylphosphatidylcholine(DPPC) upon COVID-19-related-Acute Respiratory Distress Syndrome(cvARDS). Thus, to gain a deeper understanding of the lung lipid profile upon cvARDS, we conducted a comprehensive lipidomic analysis by liquid chromatography?high-resolution mass spectrometry of bronchoalveolar lavage(BAL) samples from 6 cvARDS patients of the first wave of the pandemic, 6 non-COVID-19-patients with lung inflammation(LIP) and a control group of 12 subjects with no lung diseases(NLD). Results were normalized to the total amount of lipids. There was a significant increase in the levels of total cholesterol in cvARDS patients compared to both LIP and NLD groups [30.31(17.75-53.41)% vs 24.50(19.01-42.37)% and 15.011(12.54-18.39)% (p=0.038)] along with a tendency to increase the free cholesterol/DPPC ratio (p=0.080). Moreover, when lipid subclasses were analysed, we detected several significant changes in cvARDS when compared to the other groups: a decrease in PC32:1 [(6.08(2.08-7.73)% vs 10.78(7.14-13.53)% and 14.48(11.58-17.73)% (p=0.001)], PC34:0 [2.35(1.75-4.21)% vs 3.83(1.84-4.59)% and 5.19(4.12-5.96)% (p=0.020)], PG32:0 [5.96(2.24-8.55)% vs 10.58(8.08-41.59)% and 9.65(7.16-11.70)% (p=0.047)] and PG36:1 [(6.76(2.63-13.52)% vs 13.23(8.30-16.37)% and 15.53(13.99-18.64) (p=0.005)]. A significant increase in polyunsaturated PC36:3 was also observed [3.28(2.77-4.38)% vs 1.36(0.97-2.68)% and 1.25(0.78-2.02)% (p=0.005)]. Our findings provide new insights into the role of lipids in the respiratory response to SARS-CoV-2 infection, suggesting how perturbations in the lung lipid profile may have been involved in the pathogenesis of cvARDS.