Fbrinogen:fibrin complexes have been previously described in various thrombotic disorders. To evaluate further the properties of fibrinogen:fibrin complexes, and theirin vitro and in vivo behavior, soluable fibrinogen:fibrin complexes have been formed invitro using mixtures of '131l-fibrinogen ('131l-F) and '125l-fibrin ('125l-fb). By means of Sepharose 4B chromatography, a macromolecular complex (peak one) containing both moieties could be separated from a lower molecular weight peak two containg noncomplexed material. The latter eluted at the same position as did intact fibrogen. Both the '131l-F and '125l-fb components of peak one were rapidly catabolized when injected into rabbits with residual blood activity at 24 hours of 8 per cent and 4 per cent, respectively. Peak two behavedas a simple mixture with corresponding 24-hour levels at 31 per cent and 3 per cent. Gel filtration of postinjuection plasma samples demonstrated that peak one remained as macromolecular complex. Preinjection crosslinking of the F:fb complex with factor xiii did not substantially change the blood clearance. Prior blockage of the reticuloendotheial system with Thorotrast or carbon resulted in impaired clearance of peak one. The data provide evidence that fibrinogen and fibrin can form a macromolecular complex which is stable both in vitro and vivo. Further, the reticuloendotheialsystem was shown to mediate the the in vivo clearance of this complex. This latterfinding may be of pathophysiologic significance.