Multifocal intestinal infarctions, due to thrombosis in small vessels, might be a pathogenetic mechanism for Crohn's disease (CD). Deficiency of free protein S may contribute to the development of such thrombotic occlusions. In the present study free protein S was measured in 54 patients with CD. In 31 patients (57.4%) the plasma concentrations of free protein S were below the lower normal range. The mean value of free protein S in CD patients was 72.2%, as compared with 97.5% in healthy subjects (p < 0.01). The concentrations of C4b-binding protein and protein C were similar in the two groups. Free protein S levels were not correlated to disease activity, previous surgery or complications, extraintestinal manifestations, or current medical therapy. The impairment of the protein S/protein C/thrombomodulin system found in patients with CD favours coagulation and might be of importance for both the development of CD and its thromboembolic complications.