Treatment for GIST focuses on tyrosine kinase inhibitors (TKI), whose selection depends on specific mutations. We sought to determine the clinical utility of liquid biopsy in advanced GIST. Liquid (n=181) (FoundationOne®Liquid CDx) and tissue (n=2,198) (FoundationOne® and FoundationOne®CDx) CGP of GIST were evaluated. The presence of circulating tumor DNA in liquid was determined via tumor fraction (TF), with elevated TF defined as TF ≥1%. Liquid CGP revealed 30% (54/181) of samples had an elevated TF, among which the prevalence of KIT and PDGFRA alterations were 89% (48/54) and 2% (1/54), respectively. In patient-matched tissue/liquid samples (n=49), positive percent agreement of driver alterations in liquid with elevated TF relative to tissue was 100%. 55% (42/77) of liquid samples with a KIT-driver mutation had a co-occurring imatinib-resistant alteration; a minority of cases harbored non-KIT mechanisms of resistance such as FGFR2 fusion, BRAF or EGFR alterations. The relative prevalence of imatinib-resistance KIT exon 13 and 17 mutations was enriched in liquid compared to tissue. Finally, in the liquid cohort, 2.2%, 1.7% and 1.1% of patients were predicted to harbor germline KIT, SDHx, or NF1 mutations, respectively. In conclusion, known driver and TKI-resistant mutations were identified in liquid biopsies of GIST patients with high concordance to tissue in the presence of elevated TF. Liquid biopsy may be valuable in the molecular classification and medical management of GIST.