Alpha-fetoprotein (AFP), a fetal protein associated with certain tumors, and serum albumin did not corssreact immunologically in native form. Unfolding of their polypeptide chains by reduction of the disulfide bonds followed by carboxamidomethylation produced derivatives with immunochemical properties different from those of the native proteins. Precipitating reactions and radioimmunoassays preformed with antibodies to such unfolded derivatives showed strong crossreactions between albumin and AFP. These assays were found to lack species specificity: AFPs and albumins from different species were equally active. Several other proteins unrelated to AFP or albumin did not react or reacted much less in these assays. These results support the conclusions derived from recent sequence data that AFP and albumin are structurally related and have a common ancestral gene.