On the basis of structural studies of both degrading insoluble cross-linked fibrin and of soluble derivatives, we have developed a model to explain the principal structural and physical features of plasmic degradation of cross-linked fibrin in vitro from the completely intact matrix to terminally degraded soluble derivatives. The critical event of solubilization occurs only as the result of coincident cleavages at complementary sites in the basic two-stranded half-staggered overlap fibrin structure, resulting in the release of two-stranded complexes held together by noncovalent forces. The four smallest complexes that are released into solution have structures corresponding to DD/E, DY/YD, YY/DXD, and YXD/DXY. The protein initially solubilized has a constant composition with a predominance of large derivatives that are composed of at least one fragment from each of the two strands of the protofibril. Following their release into solution the larger complexes are converted in vitro to smaller ones by the continued action of plasmin, so that the complex found following prolonged digestion is DD/E. It is proposed that this newly defined group of complexes represents the major form of circulating plasmic derivatives of cross-linked fibrin.