OBJECTIVE Intermittent pneumatic compression (IPC) increases systemic fibrinolytic activity but may also injure endothelial cells and thereby induce coagulation. The safety and utility of IPC in patients with peripheral arterial disease (PAD) therefore remains uncertain. The aim of this study was to determine whether IPC is associated with coagulation activation and endothelial cell damage, platelet factor 4 (PF4), thrombin-antithrombin complex (TAT), total nitrate and nitrite level and von Willebrand factor (VWF) concentration. METHODS PF4, TAT, total nitrate, nitrite level and VWF were analyzed before and after first, 5th, 15th session (1 hour/day) of IPC and then 3 weeks after completion of therapy in 25 claudicants and compared to 11 healthy volunteers of similar age and sex. RESULTS PF4, a measure of platelet activation/secretion, was significantly higher in claudicants (55+/-50 IU/mL) compared to healthy controls (22+/-14 IU/mL) (P<0.05). In PAD patients PF4 has decreased steadily and significantly throughout the time of compressive therapy (to 33+/-42 IU/mL) and further more at the end of the follow-up period (23+/-26 IU/mL). TAT concentration was low in PAD patients but further decreased during IPC therapy. There was a tendency of nitrite and nitrate concentration to increase during the course of IPC therapy, but in PAD patients it did not reached statistical significance (P=0.2), while in healthy controls this increase was significant (up to 79+/-14 mmol/L, P<0.05) and persisted 3 weeks after completion of IPC (up to 82+/-7 mmol/L, P<0.05). VWF antigen concentration remained stable in claudicants during IPC therapy and 3 weeks later but significantly decreased during IPC therapy (after fifth and fifteenth IPC session, P=0.04) and stayed decreased 3 weeks after treatment termination in control group. Pain-free walking distance (PWD) had increased continuously during treatment period from 55+/-23 to 63+/-32 meters after fifth IPC treatment, to 81+/-43 (P<0.05) after the last session of therapy, and slightly decreased to 77+/-28 meters 3 weeks after completion of IPC. CONCLUSIONS IPC is safe for PAD patients, does not activate coagulation, but decreases platelet activation and improves endothelial health; this coincides with significant prolongation of walking distance.