Severe combined immunodeficiency (SCID) is a treatable, inherited lack of cellular and humoral immunity caused by diverse mutations in several different genes and leading to death in infancy unless immune reconstitution is provided. Currently no population screening exists for SCID, but early diagnosis would improve outcome.Because all patients with SCID make few or no T cells, we asked whether the absence of T-cell receptor excision circles (TRECs), DNA episomes in newly formed T cells, could identify SCID regardless of genotype.DNA isolated from dried blood spots was assayed by real-time PCR to quantitate TRECs. Control PCR was performed on a segment of the beta-actin gene. After pilot studies with adult and cord blood control subjects, blood from SCID patients was spotted onto filters and tested, followed by screening of actual blood spots from the Maryland Newborn Screening Program. Finally, newborn blood spots were recovered and tested from 2 infants after their diagnosis of SCID.In contrast to filters from the newborn screening program, which had a mean of 1020 TRECs in two 3-mm punches, samples from 23 infants with SCID had <30 TRECs. The newborn screening filter was retrieved from a state laboratory for one of these infants plus another infant who had died of SCID previously; although both samples had detectable beta-actin DNA, neither had TRECs.TRECs are a stable analyte that can identify T-cell lymphopenia in newborn dried blood spots so that infants with SCID can receive early, life-saving treatment.