Importance: Patients with advanced soft-tissue sarcomas (STS) have a median overall survival of less than 18 months. Identification of molecular abnormalities for which targeted therapies are available or can be developed is critical for improving patient outcomes. Objective: To characterize targetable genomic alterations (GAs) in patients with STS. Design, Setting, and Participants: This cross-sectional study of next-generation sequencing results from 584 patients with STS included in the AACR GENIE Database. Main Outcomes and Measures: Presence of targetable GAs in STS. Results: Of 584 patients included in the analysis, 294 (50.3%) were men and 290 (49.7%) were women, with a median age of 56 years (range, 18-89 years). There were 331 (57%) patients with complex genomics sarcomas, 144 (25%) with translocation-related sarcomas, and 112 (18%) with other sarcomas (inactivating mutation, simple amplicon). A total of 2697 alterations were identified in 451 genes (1154 substitutions, 765 gene amplifications, 364 short indels and splicing variants, 346 gene homozygous deletions, and 68 gene rearrangements) with a median of 4 (1-53) per case. In order of frequency, the 20 genes most often altered were: TP53, MDM2, CDK4, RB1, ATRX, CDKN2A, PTEN, NF1, CDKN2B, KMT2D, GLI1, ATM, TERT, PI3KCA, NOTCH1, MAP2K4, ERBB4, ARID1A, TSC2, and TNFAIP3. At least 1 targetable GA was found in 239 cases (41%) with a statistically significant higher number in other and complex genomics sarcomas than in translocation-related sarcomas (respectively other: n=89, 82%, complex: n = 131, 40%, translocation: n = 19, 13%; chi2 test, P < .001). Conclusions and Relevance: Up to 41% of STS harbored at least 1 clinically relevant GA with potential to influence and personalize therapy. Comprehensive genomic profiling can identify novel treatment paradigms to address the limited options and poor prognoses of patients with STS.Read less <