Natural heterophile immunity was studied in 949 individuals including 41 recipients and donors of renal transplants and 141 families. The prevalence and strength of the natural immunity was at its maximum during the first two decades of life and declined thereafter. The population could be divided into three groups: one with natural immunity to heterophile transplantation antigens (HT-A), one with a heterophile immunity which was not (anti-HT-A) (i.e., anti-HX-A), and one group which had no heterophile immunity. Transplantation among these groups yielded results which along with family studies and mathematical considerations suggest that the HT-A system is controlled by a single genetic locus comprised of one dominant and one recessive allele.