X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by mutations in the Bruton tyrosine kinase (
BTK
) gene leading to B lymphocyte deficiency and susceptibility to infection. A potential benefit of earlier diagnosis and treatment initiation on morbidity and mortality in XLA is incompletely understood. In the USIDNET Registry, we describe infection frequency and infection-related mortality in patients with XLA and their relationship to age of diagnosis and treatment initiation. Among the 231 XLA patients enrolled in the Registry, respiratory infections (
N
= 203, 88%) were the most commonly reported. Among those deceased (
N
= 20) where cause of death was known (
N
= 17), mortality was attributed to infection in most (
N
= 12, 71%). Chronic lung disease, often a consequence of repeated lower respiratory tract infection (LRTI), was also a frequent complication associated with mortality (
N
= 9, 53%). Age of diagnosis in years was lower for those without LRTI compared to those with (median 1.5 [IQR 0.5–3.3] vs. median 3.0 [IQR 1.0–5.0],
p
= 0.0026) and among living patients compared to deceased (median 1.8 [IQR 0.5–5.0] vs. median 2.7 [IQR 1.6–6.0],
p
= 0.04). Age at treatment initiation in years was lower among those without LRTIs compared to those with (median 1.0 [IQR 0.4–2.4] vs. median 2.8 [IQR 1.0–5.4],
p
= 0.0006). For every year increase in age at start of therapy, the odds of experiencing a LRTI was 1.216 (OR 1.216, 95% CI 1.048–1.411,
p
= 0.01). Given the expected finding of reduced LRTIs and mortality among those with earlier age at diagnosis, our study findings support inclusion of XLA in newborn screening programs.
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