Background: Novel prognostic and predictive biomarkers beyond traditional histological subtypes are needed to better inform outcomes and enhance therapy guidance in breast cancer (BC). We have previously reported that ILF2 was overexpressed in TNBC cell lines and has a functional role in DNA and RNA metabolism, making it a promising biomarker for risk assessment and treatment decisions. Herein, we aim to leverage a large clinico-genomic dataset to further characterize ILF2 in BC patients (pts). Methods: A total of 9456 BC tissue samples underwent molecular profiling at Caris Life Sciences (Phoenix, AZ). Analyses included next generation sequencing of DNA (592 Gene Panel, or Whole Exome Sequencing), and RNA (Whole Transcriptome Sequencing), and immunohistochemistry (IHC). Wilcoxon and Fisher’s exact were used to determine statistical significance. Overall survival (OS) was obtained from insurance claims and Kaplan-Meier estimates were calculated. Spearman correlation was used to identify highly correlated genes (ρ>0.6) with ILF2 and significant genes that were subsequently analyzed via pathway analysis using STRING. Results: BC pts were grouped into ILF2-High (H, top quartile) and ILF2-Low (L, bottom quartile) based on mRNA expression (TPM). ILF2-H pts were significantly younger (73 vs 80% for pts >50), enriched in ductal histology (90.9 vs 77.7%), TNBC subtype (48.9 vs 18.9%), and had a higher CNS metastases rate (4.3 vs 1.4%) compared to ILF2-L pts (all q<0.0001). ILF2 overexpression was associated with significantly inferior OS in all BC pts (HR 3.38, 95%CI: 2.97 – 3.84); when stratified into known BC hormonal receptor (HR) subtypes, ILF2 was prognostic in both HR+ BC (HR 1.7, 95 CI: 1.34-2.19) and TNBC (HR 3.8, 95 CI: 3.1-4.7), all p<0.0001. In TNBC (n=2468), ILF2-H was associated with a higher frequency of TP53 mutations(mt), lower rate of PIK3CA mt and higher amplification of CCNE1 and FGF23; in HR+/HER2- BC (n = 5071), an association with a higher rate of TP53 mt, PD-L1 expression, NOTCH2 and CCND2 amplification was seen (Table). No significant molecular correlation with ILF2 was seen in HR-/HER2+ BC (n=682). In TNBC, ILF2 expression was significantly correlated with genes involved in spliceosome, cell cycle and RNA transport pathways. In HR+/HER2- BC, ILF2-correlated genes were significantly enriched in mismatch repair and DNA replication pathways (p<0.05 for all factors individually). Conclusions: High expression of ILF2 is associated with a poorer prognosis independent of subtype in BC and our study warrants further investigation on ILF2 as a diagnostic and therapeutic target.