We report two distinct variants affecting the beta IV domain of erythrocyte spectrin, designated spectrin Saint-Chamond and spectrin Tlemcen. They were discovered in a French family and an Algerian individual, respectively. They appeared clinically and morphologically asymptomatic in the heterozygous state. In two-dimensional maps of spectrin partial digests, both mutants were manifested by cathodic shifts (with no change of the molecular weights) of the peptides that cover the N-terminal region of spectrin beta IV domain. The relevance of the abnormal peptides to the beta IV domain was established by quantitative analysis and by Western blotting using anti-beta IV domain-specific antibodies. These two variants are thus far the most distal variants of spectrin to be defined on an unequivocal structural basis.