Evidence for a new HLA class II specificity is presented. It is recognized by LE serum, which reacts with most DR1 and/or DR4 individuals (r = 0.86). Its frequency in the French population is 0.33. Absorption-elution experiments showed that the serum reactivity was not due to a mixture of anti-DR1 and anti-DR4 antibodies, but to a single antibody population which could be absorbed on and eluted from both DR1(+) or DR4(+) cells. LE specificity seemed to be expressed on DR but not on DQ molecules since the serum reacted with and could be absorbed by DR+,DQw- cells; it did not react with a DR-,DQw+ mutant cell, but did react with the DR+,DQw+ parental cell. The relationship between LE specificity and MC1 and Te23 specificities remains to be determined.