Ambulatory oxygen therapy is often provided to patients with interstitial lung disease (ILD). Lightweight portable oxygen concentrators (POCs) provide an alternative to traditional portable systems such as compressed oxygen cylinders; however, their efficacy in patients with ILD has not been assessed. This study aimed to evaluate the clinical performance of three ambulatory oxygen systems (two different POCs and a compressed oxygen cylinder) during 6-min walk tests (6MWTs) in patients with ILD and exertional desaturation.A total of 20 participants with ILD of varying aetiologies who demonstrated exertional desaturation to <90% on room air during 6MWT were recruited. Each participant performed two 6MWTs while breathing room air. On a subsequent day, two further 6MWTs were performed, in random order: one breathing oxygen via a POC (either the Inogen One G2 POC or the EverGo POC at the setting of 6) and one with a compressed oxygen cylinder (at 5 L/min).There were no significant differences in nadir oxygen saturation (SpO2 ) during 6MWTs using different portable oxygen devices (Trial 1: mean SpO2 for Inogen One G2 POC: 82.3 ± 3.5% vs oxygen cylinder: 80.3 ± 2.2%, P = 0.14; Trial 2: mean SpO2 for EverGo POC: 85.7 ± 7.7% vs oxygen cylinder: 86.1 ± 6.1%, P = 0.79). The mean 6-min walk distances were not significantly different among the three devices.The performance of the Inogen One G2 POC and the EverGo POC had comparable performance with that of the compressed oxygen cylinder during walking in patients with ILD and exertional desaturation.