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Abstract Children with life-threatening asthma exacerbations who are admitted to a pediatric intensive care unit (PICU) are a heterogeneous group with poorly studied inflammatory features. We hypothesized that distinct clusters of children with asthma in a PICU would be identified based on differences in plasma cytokine levels and that these clusters would have differing underlying inflammation and asthma outcomes within 1 year. Plasma cytokines and differential gene expression were measured in neutrophils isolated from children admitted to a PICU for asthma. Participants were clustered by differential plasma cytokine abundance. Gene expression differences were compared by cluster and pathway over-representation analysis was performed. We identified two clusters in 69 children with no clinical differences. Cluster 1 (n = 41) had higher cytokines compared to Cluster 2 (n = 28). Cluster 2 had a hazard ratio of 2.71 (95% CI 1.11–6.64) compared to Cluster 1 for time to subsequent exacerbation. Gene expression pathways that differed by cluster included interleukin-10 signaling; nucleotide-binding domain, leucine rich repeat containing receptor (NLR signaling); and toll-like receptor (TLR) signaling. These observations suggest that a subset of children may have a unique pattern of inflammation during PICU hospitalization that might require alternative treatment approaches.