Abstract Introduction. PredicineCARE is a CLIA-certified targeted next-generation sequencing (NGS) assay that provides comprehensive, non-invasive genomic profiling of circulating tumor DNA (ctDNA) in blood and urine. Here we present liquid biopsy mutational profiles and genome-wide cell-free DNA (cfDNA) copy-number burden levels for historical cancer cohorts analyzed with PredicineCARE. We include a total of 3,147 samples from six major cancer indications: prostate (n=1681), lung (n=630), breast (n=300), colorectal (n=217), pancreatic (n=190), and bladder (n=129). Methods. PredicineCARE employs a 152 targeted gene panel covering all major guideline-recommended alterations for patient care and clinical drug development including targeted therapies and immunotherapies. The assay detects single nucleotide variants (SNVs), small insertions and deletions, gene-level copy number loss/gain, and targeted re-arrangements/fusions. Concurrent low-pass whole-genome sequencing (without the need for additional sample volume) is performed to measure blood-based genome-wide copy-number burden (bCNB) and tumor fraction, providing important complementary molecular insights to variant detection. Results. We present data from a representative cohort of blood and urine samples processed at Predicine lab in Hayward California (n=3,147). Sequencing was performed using a minimum of 5 ng total cfDNA input from 1-5 mL of plasma or 20-40mL of urine, at one or more clinical timepoints per patient. Samples were sequenced at ~20,000X target panel coverage and the majority also had ~2.5X low-pass whole genome sequencing. Using the Predicine in-house DeepSea bioinformatics pipeline, we report variants as low as 0.05% allele frequency and estimate genome-wide CNVs and bCNB from low-pass data. We compare the mutational and CNV profiles of important genes in each liquid biopsy cancer cohort to variants reported in solid tumor tissues from several large public data sets including Project GENIE (n=71,817 patients) and 136 additional study programs including TCGA (n=38,619 patients, www.cBioPortal.org). Conclusion. PredicineCARE is a highly sensitive and robust assay for detecting cancer variants in blood and urine. The cfDNA mutation profiles are mostly consistent with public tissue datasets. A small but significant portion of the detected ctDNA variants have been shown to be important for treatment selection or are currently being tested for targeted drug development. Increased bCNB provides a useful measure to monitor treatment response and disease progression. PredicineCARE has been CE-marked and received breakthrough device designation from FDA. A harmonized PredicineCARE assay is available in the US and China to support patient testing in the clinic, global clinical trials and CDx development. Citation Format: Billie Gould, Lu Tan, Chao Dai, Tiantian Zheng, Wei Mo, Xianghong Wang, Michael Sneddon, Shidong Jia, Kemin Zhou, Pan Du. Targeted liquid biopsy mutation profiling and genome-wide cfDNA copy-number landscape in 3000 samples from six major cancer indications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6685.