Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) is a protein that potently attenuates fibrinolysis. A considerable proportion of its variability levels is genetically determined. It has been associated with arterial and venous thrombosis. We conducted a Genome Wide Scan for genes affecting variation in plasma TAFI levels in 398 subjects from 21 extended Spanish families. The data were analyzed by a variance-component linkage method. A strong linkage signal was found on the long arm of Chromosome 13, near the DNA marker D13S156, where the structural gene encoding for TAFI is located. In addition, other new linkage signals were detected on chromosome regions 5p and 7q. More importantly, we performed another multipoint linkage analysis of functional TAFI conditioned on TAFI antigen levels. We detected a strong linkage signal on Chromosome 19 (LOD = 3.0, P = 0.0001) suggesting a novel QTL in this region involved in the specific functional activity of TAFI, regardless of the TAFI antigen levels. One notable aspect of this study is the identification of new QTLs that reveal a clearer picture of the genetic determinants responsible for variation in TAFI levels. Another is the replication of the linkage signal of the CPB2 gene, which confirms an important genetic determinant for TAFI antigen levels. These results strongly suggest an oligogenic mode of inheritance for TAFI, in which CPB2 gene accounts for a proportion of the variation of the phenotype together with other unknown genes that may represent potential risk factors for thrombotic disease.