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Background: The incidence, causes and impact of diaphragm thickness evolution in veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for cardiogenic shock are unknown. Our study investigates its evolution during the first week of VA-ECMO and its relationship with sweep gas flow settings. Methods: We conducted a prospective monocentric observational study in a 12-bed ICU in France, enrolling patients on the day of the VA-ECMO implantation. The diaphragm thickness and the diaphragm thickening fraction (as index of contractile activity, dTF; dTF < 20% defined a low contractile activity) were daily measured for one week using ultrasound. Factors associated with diaphragm thickness evolution (categorized as increased, stable, or atrophic based on > 10% modification from baseline to the last measurement), early extubation role (< day4), and patients outcome at 60 days were investigated. Changes in diaphragm thickness, the primary endpoint, was analysed using a mixed-effect linear model (MLM). Results: Of the 29 included patients, seven (23%) presented diaphragm atrophy, 18 remained stable (60%) and 4 exhibited an increase (17%). None of the 13 early-extubated patients experienced diaphragm atrophy, while 7 (46%) presented a decrease when extubated later (p-value = 0.008). Diaphragm thickness changes were not associated with the dTF (p-value = 0.13) but with sweep gas flow (Beta = − 3; Confidence Interval at 95% (CI) [− 4.8; − 1.2]. p-value = 0.001) and pH (Beta = − 2; CI [− 2.9; − 1]. p-value < 0.001) in MLM. The dTF remained low (< 20%) in 20 patients (69%) at the study's end and was associated with sweep gas flow evolution in MLM (Beta = − 2.8; 95% CI [− 5.2; − 0.5], p-value = 0.017). Odds ratio of death at 60 days in case of diaphragm atrophy by day 7 was 8.50 ([1.4–74], p = 0.029). Conclusion: In our study, diaphragm thickness evolution was frequent and not associated with the diaphragm thickening fraction. Diaphragm was preserved from atrophy in case of early extubation with ongoing VA-ECMO assistance. Metabolic disorders resulting from organ failures and sweep gas flow were linked with diaphragm thickness evolution. Preserved diaphragm thickness in VA-ECMO survivors emphasizes the importance of diaphragm-protective strategies, including meticulous sweep gas flow titration. Key points: Question: How does the diaphragm thickness evolves during the first week of VA-ECMO treatment for a cardiogenic shock and is it associated with sweep gas flow settings? Findings: In patient receiving VA-ECMO for a cardiogenic shock, fewer progressive atrophy was described when early extubation was possible and associated with lower death rate at two months. The diaphragm thickness increased with the sweep gas flow and decreased with the acidosis. Diaphragm thickness evolution did not evolve parallel to the diaphragm thickening fraction. Meaning: In VA-ECMO-treated patients, we advocate for diaphragmatic-protective strategies through the careful titration of sweep gas flows, tight pH control, and the promotion of early extubation. [ABSTRACT FROM AUTHOR]