In the United States, newborn screening (NBS) is currently recommended for identification of 31 debilitating and potentially fatal conditions. However, individual states determine which of the recommended conditions are screened. The addition of severe combined immunodeficiency (SCID) screening to the recommended NBS panel has been fully instituted by 18 states, with another 11 states piloting programs or planning to begin screening in 2014. Untreated, SCID is uniformly fatal by 2 years of age. Hematopoietic stem cell transplantation usually is curative, but the success rate depends on the age at which the procedure is performed. Short-term implementation costs may be a barrier to adding SCID to states' NBS panels. A retrospective economic analysis was performed to determine the cost-effectiveness of NBS for early (<3.5 months) versus late (≥3.5 months) treatment of children with SCID at 3 centers over 5 years. The mean total charges at these centers for late treatment were 4 times greater than early treatment ($1.43 million vs $365,785, respectively). Mean charges for intensive care treatments were >5 times higher ($350,252 vs $66,379), and operating room-anesthesia charges were approximately 4 times higher ($57,105 vs $15,885). The cost-effectiveness of early treatment for SCID provides a strong economic rationale for the addition of SCID screening to NBS programs of other states.