Recently, high levels of coagulation factor (F)VIII, FIX and FXI have been associated with an increased risk of venous thrombosis. For several coagulation factors a substantial hereditary component was found. If regulatory genes are located outside the clotting factor genes, they may regulate the levels of several proteins in the coagulation system. Thus levels would then cluster in individuals. The aim of the present study was to assess the inter-relation among levels of the pro- and anticoagulant proteins in the coagulation cascade. We also investigated the relation between the coagulation factors and d-dimer levels (marker of coagulation activity). All analyses were performed in healthy subjects, the control population of the Leiden Thrombophilia Study (LETS), to eliminate the influence of a prior thrombosis on the interpretation of the results (n = 466). Using principal-components analysis, a method intended to explain relationships among several correlated variables, we found a clustering between the vitamin K-dependent factors (prothrombin, VII, IX, X) and FXI and FXII. FV and FVIII clustered with fibrinogen and d-dimer. FXIII remained relatively independent of the other factors. Adding the anticoagulant factors to the analysis resulted in minor changes in the clustering pattern. The anticoagulant factors clustered together. We found relatively independent clusters within the group of pro- and anticoagulant factors, which may suggest that the genetic basis for high or low levels of factors in the coagulation system may, at least partly, lie outside the genes coding for these factors.