Chemotherapy is an indispensable method in treatment of Soft tissue sarcomas (STS), but variability in sensitivity as a result of tumor heterogeneity is a key factor in determining patient outcome. Several studies have investigated the phenomenon of chemotherapy resistance in STS, while its precise complex mechanism is still unknown. This study aims to identify potential biomarkers for predicting the STS chemosensitivity, with the goal of both aiding patient treatment determination in the clinic and providing insight into key parts of the underlying mechanism. Gene expression profiles of 265 patients were obtained from The Cancer Genome Atlas dataset and differentially expressed genes (DEGs) associated with chemosensitivity were identified in groups of varying chemosensitivity, including 177 upregulated and 21 downregulated genes (P < 0.05). Then, DEGs were found to be enriched in complement and coagulation cascades and the osteoclast differentiation pathway. Protein-protein interaction analysis showed 15 genes (52 edges) enriched in the complement and coagulation cascades while 11 genes (28 edges) enriched in the osteoclast differentiation pathway. Notably, all the genes that significantly correlated to disease-free survival (DFS) and overall survival (OS), such as C1QC, C3AR1, C7, CFI and SERPINE1, are enriched in complement and coagulation cascades pathway. The differential expression of these genes was further verified by using the GSE database. Our findings support that C1QC, C3AR1, C7, CFI and SERPINE1 in the complement and coagulation cascade pathway are potential biomarkers for chemotherapy resistance and survival of STS patients.