PURPOSE: Chromosome 22q11.2 deletion syndrome (22q11.2DS), the most common cause of DiGeorge syndrome, is quite variable. Neonatal diagnosis traditionally relies on recognition of classic features and cytogenetic testing, but many patients come to attention only following identification of later onset conditions, such as hypernasal speech due to palatal insufficiency and developmental and behavioral differences including speech delay, autism, and learning disabilities that would benefit from early interventions. Newborn screening (NBS) for severe combined immunodeficiency (SCID) is now identifying infants with 22q11.2DS due to T cell lymphopenia. Here, we report findings in such neonates, underscoring the efficacy of early diagnosis. METHODS: A retrospective chart review of 1350 patients with 22q11.2DS evaluated at the Children's Hospital of Philadelphia identified 11 newborns with a positive NBS for SCID. RESULTS: Five out of 11 would have been diagnosed with 22q11.2DS without NBS, whereas early identification of 22q11.2DS in 6/11 led to the diagnosis of significant associated features including hypocalcemia, congenital heart disease (CHD), and gastroesophageal reflux disease that may have gone unrecognized and therefore untreated. CONCLUSIONS: Our findings support rapidly screening infants with a positive NBS for SCID, but without SCID, for 22q11.2DS even when typically associated features such as CHD are absent, particularly when B cells and NK cells are normal. Moreover, direct NBS for 22q11.2DS using multiplex qPCR would be equally, if not more, beneficial, as early identification of 22q11.2DS will obviate a protracted diagnostic odyssey while providing an opportunity for timely assessment and interventions as needed, even in the absence of T cell lymphopenia.