Aim: To investigate the concentration of natural anticoagulants protein C (PC) and tissue plasminogen activator (t-PA) in patients with rheumatoid arthritis (RA) and to evaluate the effect of their concentration on the course of the disease. Materials and Methods: We examined 74 patients with RA. There were 15 men and 59 women and control group consisted of 27 subjects. The average age of the patients was 47.3±1.12 years. Laboratory (PC, t-PA, C-reactive protein, TNF-alpha, von Willebrand factor, and lipid profile) and instrumental (ultrasonography and Doppler) examinations were performed. Results: PC deficiency was significantly more common among men with RA (26.6%), but did not depend on the age and the duration of the disease (p<0.05). PC deficiency correlates with the degree of activity of the inflammatory process (r = -0.27) and TNF-alpha (r = -0.37). The levels of PC and t-PA were associated with the level of cholesterol (r = -0.25), LDL-C (r = -0.31), and HDL-C (r = 0.31). In patients with PC and t-PA deficiency, significantly higher (by 19% and 12%, respectively) serum levels of Von Willebrand factor were recorded than in patients with normal levels (p<0.05). Conclusions: The study of P. and t-PA revealed a deficiency of important natural anticoagulants, that helps us to expand the understanding of the mutually aggravating effect of the deficiency of these compounds and changes in known biologically active substances on the course of RA, and to supplement the pathogenetic picture of RA with certain links.