The properties of brain fodrin have been analyzed and compared with those of erythrocyte spectrin. Both proteins consist of high molecular weight polypeptide doublets on SDS polyacrylamide gels and in solution behave as very large asymmetric molecules. Both proteins show a characteristic increase in sedimentation coefficient in the presence of 20 mM KCl. Antibodies against the brain protein cross-react with erythrocyte spectrin and cross-react with similar high molecular weight doublet polypeptides in SDS polyacrylamide gels of other cell types and plasma membrane preparations. Both proteins bind actin. The brain protein and erythrocyte spectrin show specific and competitive binding to erythrocyte membranes and this binding is inhibited by antibodies against erythrocyte ankyrin. Several of these properties distinguish these proteins from the class of high molecular weight actin-binding proteins that includes filamin and macrophage actin-binding protein. We conclude that together with erythrocyte spectrin, the brain protein and equivalent, immunologically related proteins in other cell types belong to a single class of proteins with the common function of attachment of actin to plasma membranes. Based on the structural and functional similarities, the name spectrin would seem appropriate for this whole class of proteins.