The red cells from a 23-year-old pregnant woman gave very unusual blood grouping reactions and her serum contained a ‘new’ antibody active against a very high incidence antigen. The reactions of various unrelated blood group antigens are modified, in some cases enhanced and in others depressed, the total picture being strongly reminiscent of the effects of proteolytic enzyme treatment. It is suggested that these effects can only be due to some factor affecting the red cell structure possibly by modifying the cell envelope. This modifying factor is genetically determined and shows dosage effect. Of nine siblings three are apparently homozygous and four heterozygous for this factor, the other two being ‘normal’. It is extremely rare, no further examples having been found in 18,472 blood donors. The antibody is undoubtedly immune, probably due to a blood transfusion two years previously. 12,509 donors have been tested with it but the only compatible red cells are those of the three homozygous siblings, i.e. the propositus, one sister and one brother. The antibody is therefore related to the modifying factor. Two codominant genes En^a and En^b are postulated, En^b being exceedingly rare. It is suggested that these genes determine not only the presence of the corresponding antigens Ena and Enb but also the structure of the red cell. EnaEna = ‘Normal’. EnaEnb = ‘Single dose modified’. EnbEnb = ‘Double dose modified’. The antibody thus becomes anti-En^a.