We carried out experiments to determine conditions for fibroblast adhesion to fibrinogen and fibrin substrata. Baby hamster kidney (BHK) cells did not attach to substrata composed of purified fibrinogen or fibrin. When cold-insoluble globulin (CIG) (plasma fibronectin) was bound to fibrinogen or fibrin substrata, adhesion of BHK sells was observed and the extent of adhesion was dependent upon the CIG conecntration. Binding of CIG to fibrinogen or fibrin substrata in the presence of Factor XIII (factor) under covalent crosslinking conditions resulted in a marked increased in the ability of the substrata to support cell adhesion. Control experiments indicated that CIG formed the sites on the fibrinogen and fibrin substrata to which the cells were attaching. In addition, the effect of factor XIII was shown to require covalent crossliking of CIG to the fibrinogen or fibrin, which involved a glutamine residue on the CIG molecule and could be prevented by prior crosslinking of CIG with putrescine or with itself. The enhanced ability of Factor XIII-crosslinked CIG substrata to support cell adhesion could not be accounted for by the absolute amount of CIG bound to the substrata. We present in this paper the possibility that the orientation of CIG on the substrata is the critical factor.