We detected genetically determined, electrophoretic variants of vitamin B12 binding proteins, most probably transcobalamin II, in human plasma. Polymorphic variants were observed in all populations tested; the two most common alleles (of at least four detected to date) attain frequencies of greater than 40% in Caucasians and Orientals. The variants are autosomally inherited and are seen as doublets in homozygotes, and four-banded patterns, the sum of two dissimilar homozygote patterns, in heterozygotes. The technique used in this survey, polyacrylamide gel electrophoresis (PAGE) autoradiography of plasma and serum labeled in vitro with 57Co-vitamin B12 is particularly applicable to the study of trace proteins such as the transcobalamins (10(-9)M). Possible functional variation in the TC II allele products is described, and the selective significance of this worldwide polymorphism is considered.