The proportion of spectrin tetramers and dimers in 4 degrees C low ionic strength extracts of red cell membranes of 9 subjects with 4 different variants of hereditary elliptocytosis (HE) and 2 subjects with hereditary spherocytosis (HS) was determined by nondenaturing gel electrophoresis. Such extracts reflect the native oligomeric state of spectrin in the red cell membrane. In two hemolytic HE variants (an unclassified adult with increased thermal sensitivity of red cells and an infant also showing increased thermal sensitivity of red cells), the proportion of dimers was increased, whereas the remaining subjects had values within the control range. Conversion of spectrin tetramers to dimers under isotonic conditions at 37 degrees C, or spectrin dimers to tetramers at 30 degrees C, resulted in a high proportion of dimers in the above two HE variants, as well as in a third variant with probable mild HE and sporadic hemolysis. The mother of the infant with elliptocytosis and increased thermal sensitivity of red cells, although hematologically normal, had an increased proportion of dimers in 4 degrees C low ionic strength extracts of her red cell membranes. These findings reflect an underlying primary or secondary abnormality of spectrin in these subjects that affects the association state of spectrin in the red cell membrane. Their exact relationship to the pathogenesis of the elliptical shape of the red cell, or to the presence of hemolysis, is at present unclear.