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Purpose: Radiation therapy for tumors subject to breathing-related motion during breath-holds (BHs) has the potential to substantially reduce the irradiated volume. Mechanically assisted and noninvasive ventilation (MANIV) could ensure the target repositioning accuracy during each BH while facilitating treatment feasibility through oxygen supplementation and a perfectly replicated mechanical support. However, there is currently no clinical evidence substantiating the use of MANIV-induced BH for moving tumors. The aim of this work was, therefore, to evaluate the technique's performance under real treatment conditions., Methods and Materials: Patients eligible for lung or liver stereotactic body radiation therapy were prospectively included in a single-arm trial. The primary endpoint corresponded to the treatment feasibility with MANIV. Secondary outcomes comprised intrafraction geometric uncertainties extracted from real-time imaging, tolerance to BH, and treatment time., Results: Treatment was successfully delivered in 92.9% (13/14) of patients: 1 patient with a liver tumor was excluded because of a mechanically induced gastric insufflation displacing the liver cranially by more than 1 cm. In the left-right/anteroposterior/craniocaudal directions, the recalculated safety margins based on intrafraction positional data were 4.6 mm/5.1 mm/5.6 mm and 4.7 mm/7.3 mm/5.9 mm for lung and liver lesions, respectively. Compared with the free-breathing internal target volume and midposition approaches, the average reduction in the planning target volume with MANIV reached -47.2% ± 15.3%, P < .001, and -29.4% ± 19.2%, P = .007, for intrathoracic tumors and -23.3% ± 12.4%, P < .001, and -9.3% ± 15.3%, P = .073, for upper abdominal tumors, respectively. For 1 liver lesion, large caudal drifts of occasionally more than 1 cm were measured. The total slot time was 53.1 ± 10.6 minutes with a BH comfort level of 80.1% ± 10.6%., Conclusions: MANIV enables high treatment feasibility within a nonselected population. Accurate intrafraction tumor repositioning is achieved for lung tumors. Because of occasional intra-BH caudal drifts, pretreatment assessment of BH stability for liver lesions is, however, recommended., Competing Interests: None., (© 2024 The Author(s).)