Cleavage of human fibrinogen and fibrin by plasmin is associated with modification of native antigenic expression and the exposure of cleavage-associated neoantigenic sites on the derivative molecular fragments. In this study, the presence of humoral antibodies in man to cleavage-associated neoantigens has been demonstrated by primary antigen binding radioimmunochemical assays. Specific binding of radioiodinated human fibrinogen D fragment by serum immunoglobulins was demonstrated in 52 of 59 random normal human sera and was independent of immunoglobulin concentration. Binding was mediated by F (ab)2 fragments of IgG, and specificity for neoantigens was indicated by the capacity of the D fragment but not native fibrinogen to competitively inhibit the antibody. The population distribution of antibody to these cleavage-associated neoantigens indicated the presence of a major group of individuals (77%) with a mean antigen binding capacity of 11.8 pmol/ml serum. Two minor populations with : (a) low or undetectable binding capacities (less than 6.0 pmol/ml serum) and (b) exhibiting markedly elevated binding capacities (less 18.0 pmol/ml serum) were delineated. Independent of these features, sera could also be readily separated into two groups that differed with respect to relative antibody affinity. The antibodies in most sera exhibited marked heterogeneity of binding affinity, whereas a small group of sera contained antibodies exhibiting relative homogeneity of binding affinity. Specific antibody was rather equally distributed between the major immunoglobulin classes, and in no serum was the antibody restricted to a single immunoglobulin class. Antibodies capable of binding fibrinogen fragments X, Y, and D and fibrin D fragment were detected in most sera. The quantity of antibody differed for different fragments with X greater than Y congruent to D greater than fibrin D. The presence of antibody capable of binding any single fragment was statistically correlated with the presence of antibody capable of binding other cleavage fragments. No antibody to the E fragment was detected. Antibody to cleavage fragments was not demonstrable in sera containing fibrinogen or fibrin cleavage fragments. Demonstration of this humoral immune response to the products of the fibrinolytic systems provides a new interface between the coagulation and immune system.