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Background: In patients with interstitial lung disease (ILD), decreased oxygen saturation (SpO2) reduces physical performance and causes exertional dyspnea. Portable oxygen concentrator (POC) and pursed-lip breathing (PLB) have the potential to improve these parameters in ILD patients., Objective: To evaluate the effects of PLB while using a POC during walking in ILD patients., Design: Prospective, randomized crossover trial., Methods: We compared two breathing techniques. Participants not trained in PLB received a familiarization session before the first 6-min walking test (6MWT). During the first visit, patients performed the 6MWT under natural breathing (NB1) without oxygen (O 2 ); during the second visit, they performed the 6MWT twice, once each with PLB (PLB1) and natural breathing (NB2) under O 2 supplementation, to compare the effectiveness of NB and PLB., Results: Twenty participants were recruited; half had exercise-induced desaturation (EID) and half normal SpO 2 . In the normoxemia group (NG), the difference in the 6-min walking distance (6MWD) between NB1 and PLB1 was 28.8 ± 24.0 m, indicating reduced exercise capacity in PLB1. There were no significant differences in the quadriceps tissue saturation index (TSI), SpO 2 , and 6MWD between the PLB1 and NB2 in any patient or subgroup. All participants showed a significant increase in the SpO 2 at rest, nadir SpO 2 , and mean SpO 2 during the 6MWT with PLB and NB2 using a POC than with NB1. TSI showed a significant improvement at the beginning of 6MWT in ILD patients with EID in the PLB and NB2 condition., Conclusion: Acute exposure to PLB did not improve symptoms, muscle oxygenation, or SpO 2 ; however, it decreased the walking distance in the normoxemia group. POC improved leg muscle oxygenation in ILD patients with EID. The use of PLB and POC should be prescribed according to disease characteristics and severity.