Background: Discordance in genomic profiling between tumor tissue and ctDNA can occur due to inter-patient variability in shed tumor DNA, and intra-patient variability in sources of cell-free DNA (tumor heterogeneity, metastatic variants, CHIP). TF is an aneuploidy-based estimation of tumor-specific DNA in circulation. We evaluated the impact of TF levels on overall survival (OS), mutation concordance and tumor mutation burden in tissue (tTMB) and ctDNA (bTMB) in the LUNGMAP screening study. Methods: Eligible advanced NSCLC pts had blood drawn ≤30 days of fresh tissue biopsy with no intervening therapies. Genomic profiling was done by FoundationOne CDx and FoundationOne Liquid CDx. ctDNA TF was quantified via aneuploidy using deviations in genome-wide SNP coverage or somatic allele frequencies if under aneuploidy LoD. High TF was defined as ≥10%. Concordance among driver genes, cancer genes of interest (CGoI: TP53, PIK3CA, STK11, KEAP1, RB1, PTEN, ATM, BRCA1/2), and variant subtype were assessed by the percentage positive agreement (PPA) and positive predictive value (PPV) with 95% confidence intervals (CI). OS by TF used a Cox model and log-rank test. PPA and TF among CGoIs was compared with a Wilcoxon test. Correlation between tTMB and bTMB used Lin’s coefficient (LC). Results: 167 pts met inclusion criteria; 161 had TF data with 51 (32%) ≥10% (high TF). High TF was associated with worse OS (HR: 2.06 [1.43-2.95], p<0.001). The PPA and PPV ranged from 50%-100% and 60%-100%, respectively for driver genes. The PPA was numerically larger for high versus low TF for most drivers (p=0.18) and significantly larger for all mutations and SNVs combined (Table). For CGoI, the distribution of PPA differed between high and low TF (p=0.03). The median PPA for CGoI (25^th%ile,75^th%ile) was 56% (50,87) for low TF and 100% (100,100) for high TF. PPV for CGoI did not differ by TF (p=0.20). High TF was associated with higher levels of TMB and bTMB (p<0.01 for both). TMB LC (CI) for low and high TF were 0.46 (0.27,0.61) and 0.69 (0.53,0.81). Conclusions: High TF was associated with worse OS, better PPA among CGoI, and better LC for t/bTMB. TF may improve the clinical utility of mutations detected by liquid biopsies and should be reported and considered in interpreting these results.