Characterization of shared patterns of immune responses in critical illnesses, known as "endotypes," may have therapeutic significance. Using unsupervised k-means clustering of genome-wide gene expression profiling, we derived, validated, and assigned endotype membership in 382 children with diverse critical illnesses recruited to the BASIC study. We identified two robust endotypes, BASIC endotype 1 (122, 31.9%, children) and BASIC endotype 2 (260, 68.1%, children), present in children with diverse illnesses and age groups. BASIC endotype 1 membership was associated with 4.1 days of increased duration of mechanical ventilation and a non-significant association with mortality. BASIC endotype 1 membership was associated with higher proportions of naive and resting memory CD4 T cells, lower proportions of neutrophils, and reduced expression of gene sets associated with tumor necrosis factor alpha (TNF-α), interferon-γ, interferon-α, and interleukin-6/JAK/STAT pathways in comparison with BASIC endotype 2. These BASIC endotypes may enable stratified trials of treatment for immune dysfunction.