The role of factor XII (FXII) as the main trigger of the coagulation cascade during haemodialysis has been recently challenged. Polyvinylchloride (PVC) is the standard polymer for haemodialysis circuit tubings, but its interaction with FXII has not been extensively characterized. In a modified Chandler tubing loop model using heparinized fresh human whole blood we selectively inhibited coagulation factors VII, X or XII with monospecific antibodies. Contact of whole blood with PVC induced a strong thrombin generation [thrombin-antithrombin complexes (TAT) 64 ± 24 μg/l, before <1 μg/l]. Despite this, levels of FXII coagulation activity, free FXIIa or FXIIa-C1 inhibitor complexes remained unchanged. The anti-FXII antibody abolished thrombin generation (TAT 8 ± 5 μg/l, P < 0.05) and made the free FXIIa undetectable. Inhibition of FVII did not affect coagulation activation (TAT 68 ± 26 μg/l). Our data provide definitive evidence that PVC triggers the coagulation system via FXII. However, all FXII activation markers in plasma failed to detect contact activation.