Background: The relapsed soft tissue tumors (STS) have poor prognosis and limited treatment 30 options. However, the molecular mechanism underlying recurrence and the prognostic predictor 31 for STS are unclear. 32 Methods: We enrolled 35 extremity and trunk STS patients. Tumor specimens of 20 relapsed and 33 15 primary STS underwent sequencing to detect DNA mutation, RNA expression, and DNA 34 methylation. Moreover, 206 STS cases from TCGA were utilized to construct the relapse-associated 35 risk score model (RRSM), validated using three GEO datasets. Key model genes, COL6A3, FZD7, 36 ITPKA, and PRKAG1, was validated in FFPE tissue sections from primary and relapsed STS patients, 37 confirming their potential involvement in STS recurrence. 38 Results: The primary STS exhibited an immune-enriched tumor microenvironment (TME), whereas 39 the TME of relapsed STS had features that promote tumor recurrence or metastasis. The RRSM 40 could predict relapse-free survival (RFS) in TCGA STS and performed well in the validation cohort. 41 Multivariate analysis revealed that RRSM was an independent prognostic factor. Moreover, the 42 nomogram developed had an excellent predictive ability. 43 Conclusions: This study revealed different multi-omic profiles between relapsed and primary STS. 44 RRSM is a potential prognostic predictor for STS and lays a foundation for early intervention of 45 high-risk STS patients. The expression of genes FZD7, ITPKA, and PRKAG1 may guide STS treatment 46 decisions.