Seven human gammaG-myeloma proteins which were also cryoglobulins were studied with respect to their reactivity with gammaG-globulins as well as with regard to their antigenic classification within the gammaG-heavy chain subclasses. Five of the seven cryoglobulins studied were positive in at least two of the three tests used to assay for anti-gamma-globulin activity. One protein was only weakly positive in one test system and another was negative in all test systems. The structures which were recognized by the cryoglobulins were localized to the Fc-fragment. Only primate gammaG-globulins contained these antigenic determinants and in some cases the cryoglobulin appeared to show specificity for one human heavy chain subclass over the others. Antigenic analysis revealed that four of the five cryoglobulins with definite antibody activity belonged to the gammaG3-subclass, the fifth belonged to the gammaG1-subclass. The two cryoglobulins which reacted only weakly or failed to combine with gammaG-globulins were both of the gammaG1-subclass. These findings taken together with the localization of the combining site to the Fab-fragment suggests that many of these cryoglobulins may represent antibodies to gammaG-globulin, and that the cryoprecipitate in these cases represents antigen-antibody complexes of such a nature that they precipitate only in the cold.