Hb H disease is caused by mutations involving three a-globin genes, resulting in absent a-globin chain production from them. Each patient has only one normal a-globin gene, moderate anemia, but generally is well. During infections, oxidative drug therapy, or pregnancies, the anemia can become severe enough to warrant transfusions. In adults the excess β-globin chains form β4 tetramers (Hb H). In newborns, the excess y-globin chains form y4 tetramers (Hb Bart's). In 1996, a newborn screening program for Hb H disease was initiated in CA. Annually, 530,000 newborns were screened. Initially, it was determined that Hb Bart's level at 25% or more in newborn peripheral blood, as determined by a fast moving Hb peak on an automated HPLC system, will detect newborns with Hb H disease, confirmed by DNA-based genotyping. Hb H disease is found in 1/15,000 newborns in CA. (The incidence for phenylketonuria is 1/25,000; galactosemia 1/75,000.) The prevalence varies from 1/2,500 among Chinese and Vietnamese to as high as 1/160 among Laotian newborns. From 1996-2000, only six cases of Hb Bart's hydrops fetalis syndrome caused by homozygous a°-thalassemia were diagnosed in this program. This devastating condition is often not diagnosed until late in pregnancy or even not recognized (Blood 91:2213, 1998). A newborn with the genotype of -SEA/a(tm)1" v> r,i,A,pa) succumbed to the Hb H hydrops fetalis syndrome (Brit. J. Haematol. 96:224, 1997). A baby boy with Hb H disease was found to have inherited a hitherto novel mutation in the a2-g!obin gene, ~RL/ aL°d°"'!Se"p'°a). He was severely anemic at birth, and required six transfusions during the first four months of life. Universal newborn screening for sickle hemoglobin is presently carried out in forty states, but not yet in Canada. This study shows that the same automated laboratory procedure can detect Hb H disease. These and other data illustrate the clinical relevance of diagnosis of and investigations into Hb H disease in newborns. In US states, Canadian provinces, and especially in cities where a significant proportion of the population is made up of people of southeast Asian origin, newborn screening program for Hb H disease ought to be instituted as a public health measure.