Although an acute bout of peristaltic pulse external pneumatic compression (EPC) of the lower extremities can improve vascular function, its effect on arterial stiffness remains unclear. This study aimed to investigate the acute effect of lower-limb peristaltic pulse EPC on segmental arterial stiffness. Nineteen healthy young adults (12 males and 7 females) (age: 20 ± 1 years) were allocated to undergo two experimental trials using a randomized crossover design. EPC treatment delivered at 70-80 mmHg (EPC trial) or non-compressed sham treatment (sham trial) was performed for 30 min. At baseline (Pre) and after the 30-min treatment (Post), arterial stiffness indices, including the heart-brachial pulse wave velocity (PWV) (hbPWV), brachial-ankle PWV (baPWV), heart-ankle PWV (haPWV), and the cardio-ankle vascular index (CAVI) were measured simultaneously. All parameters in the EPC trial exhibited a significant decrease (p <
0.05) at Post compared to Pre, including hbPWV, baPWV, haPWV, and CAVI. However, no such changes were observed in the sham trial. The study findings demonstrate that a single 30-min bout of lower-limb peristaltic pulse EPC can decrease arterial stiffness in healthy young adults. The observed EPC-induced decrease in arterial stiffness in various segments suggests that the beneficial vascular effect could be elicited systemically.