Intermittent pneumatic compression (IPC) to the lower limbs is widely used as a mechanical means to prevent deep vein thrombosis in hospitalised patients. Due to a theoretical concern about impairing blood flow, thromboembolic-deterrent stockings and IPC are considered contraindicated for patients with peripheral vascular diseases by some clinicians. This study assessed whether IPC would alter peripheral limb muscle tissue oxygenation (StO 2 ), and whether such changes were different during 10 minutes of sequential and single-compartment compressions. Twenty volunteers were randomised to have their left or right arm treated with a sequential or single-compartment IPC for 10 minutes, using the contralateral arm without compression as an intraparticipant control. After a five-minute wash-out period, the procedure was repeated on the same arm using the alternative mode of IPC. Both hands’ thenar muscles StO 2 was monitored every two minutes for 10 minutes using the same near-infrared spectroscopy StO 2 monitor. Both sequential (3.5%, 95% confidence intervals (CI) 2.7–4.2; p < 0.001) and single-compartment IPC (1.6%, 95% CI 0.4–2.8; p = 0.039) significantly increased muscle StO 2 within 10 minutes compared to no compression; and the increments were higher during sequential compressions compared to during single-compartment compressions (2.1%, 95% CI 0.7–3.5; p = 0.023). This mechanistic study showed that both modes of IPC increased upper limb muscle StO 2 compared to no compression, but the StO 2 increments were higher with the multiple-chamber sequential compressions mode. Contrary to the theoretical concern that IPC may impair peripheral limb tissue oxygenation, our results showed that IPC actually increases oxygenation of the peripheral limb muscles, especially during the sequential compressions mode.