A baby girl presented with symptomatic sickle cell disease exacerbated by mild hypoxemia, despite a newborn-screening diagnosis of sickle cell trait. DNA sequencing of the beta globin gene revealed that her maternal beta globin allele was normal. Her paternal allele had not only the expected sickle-trait mutation, betaGlu6Val, but also a second, charge-neutral mutation, betaLeu68Phe. Analysis of the patient's hemoglobin revealed that the double-mutant protein, which we called "hemoglobin Jamaica Plain," had severely reduced oxygen affinity. Structural modeling suggested destabilization of the oxy conformation as a molecular mechanism for sickling in a heterozygote at an ambient partial pressure of oxygen.