e20692 Background: Liquid biopsy is an evolving minimally invasive technique to detect cell-free DNA (cfDNA) and cfRNA mutations by next generation sequencing (NGS) in plasma. In our Thoracic Oncology Program, we compared plasma liquid biopsy and tissue-based NGS assay results. Methods: Circulogene Theranostics Personalized Gene Profile (CGP), a 50-gene plasma NGS panel with proprietary direct-on-specimen enrichment technology, and tissue Caris Molecular Intelligence (CMI) NGS cfDNA and cfRNA including microsatellite instability (MSI)/microsatellite stability (MSS) and total mutational burden (TMB) results were retrospectively compiled and compared upon diagnosis. Results: 106 non-surgical lung cancer patients (median age 65 years, range 27-88; 66 men, 40 women) underwent CGP testing. 49 patients had sufficient tissue for comparative CMI. MSI detected in 20.4% (10/49) by CGP; no tissue MSI was found by CMI (0/44). 3 out of 4 (75%) MSI detected by CGP had high TMB ≥ 10 mut/Mb by CMI. 75% MSS patients by CGP had low TMB (12/16). Comparative plasma versus tissue mutations findings: TP53 mutations 60.3% (64/106) CGP and 69.3% (34/49) CMI. CGP TP53 mutated patients, high TMB 70.5 % (20/34) by CMI; EGFR mutations 13.2% (14/106) CGP and 14.2% (7/49) CMI; KRAS mutations 2.8 % (3/106) by CGP versus 28.5% (19/49); one ROS1 by CGP missed by CMI and one ALK by CGP insufficient tissue CMI. A higher frequency of BRAF 16.9% (18/106), PIK3CA 28.3% (30/106), PTEN 22.6% (24/106), and MET 7.5% (8/106) alterations was identified by plasma/CGP than comparative tissue/CMI 6.1% (3/49), 2% (1/49), 6.1% (3/49), and 0% (0/49) respectively. Conclusions: Our findings indicate that Circulogene liquid biopsy NGS detected common mutations, including actionable variants in lung cancer, providing expanded and complementary tumor molecular biology and therapeutic information to tissue NGS.