Background: Osteosarcoma(OST) differs from soft tissue sarcoma(STS) in terms of pathology and chemotherapy, but there is partial overlap in targeted therapy. Few articles have described the differences in genetic profiles of OST and STS in Chinese patients based on extensive sample data, at this point, identifying the difference genomic characterization between them may provide new drug targets for clinical diagnosis and treatment. Methods: A 551-gene targeted panel of DNA-based Next Generation Sequencing (NGS) assay was performed on tumor tissue(n = 613) and plasma(n = 136) obtained from STS(n = 586) and OST(n = 163) patients, the majority were male(n = 430, 57.4%), median age was 49(range 1-87), 101 patients also measured additional 67 gene fusions based on RNA-seq in tumor samples. All variants (SNV, INDEL, CNV and fusion) were entered into the result analysis. PD-L1expression was tested by IHC(SP263). Results: The top 5 mutant genes were TP53(28%), CDK4(20%), MDM2(18%), CDKN2A(15%), CDKN2B(15%) in STS, and TP53(26%), MYC(19%), CDK4(18%), MUC16(13%), CDKN2B(13%) in OST respectively. MDM2(18% vs 10%, p = 0.030) and PTEN(11% vs 4%, p = 0.007) were significantly higher in STS, while GNAS(7% vs 3%, p = 0.045) and IDH1(5% vs 1%, p = 0.002) were more common in OST. The most frequently affected pathways were Cell cycle(42%), Genome integrity(34%), RTK signaling(27%) in STS and Cell cycle(36%), Genome integrity(33%), transcription factor(28%) in OST. Additional significantly co-altered genes were RB1/PTEN, LRP1B/FAT3, FAT2/SPTA1 in STS, and MUC16/LRP1B, LRP1B/POLE, MED12/STAG2 in OST. More rare fusions were identified in STS. Wefound 15 PTPRB fusions, 14 of which were from STS. MDM2 fusions only detected in STS, 8 of which were from liposarcoma. Almost all patients were defined as MSS(625/629), with only 4 MSI-L and no MSI-H. 2.9%(17/589) STS and 3.1%(5/163) OST scored as TMB-H(≥10.00 Muts/Mb). TP53(p＜0.001), MUC16(p＜0.001), LRP1B(p＜0.001), FAT3(p＜0.001)were more likely to appear in the TMB-H group of STS, while MUC16(p＜0.001) was more likely to appear in TMB-H group of OST. 32.3%(83/257) STS and 29.6%(8/27) OST were PD-L1-positive(PD-L1≥1%). In STS, PDCD1LG2(p＜0.001), CD274(p＜0.001) and JAK2 (p = 0.001)were more common in the PD-L1-positive group, while MDM4 (p = 0.018) and PARP1(p = 0.003)were more common in the PD-L1-negtive group. There were no statistically significant differences due to limited PD-L1 data in OST. Conclusions: The analysis revealed that there are some differences in genetic profiles between Chinese OST and STS, which may provid more precise basis for personalized targeted therapy and immunotherapy.