Objective: To explore the relationship of S100A4 and platinum resistance in ovarian cancer. Materials and Methods: S100A4 expression level in tissue slices from 35 cisplatin-sensitive ovarian cancer patients and 28 cispatin-resistant patients were analyzed by immunohistochemistry. Platinum-resistant cells CP70 transfected with S100A4 siRNA were set as experimental group, negative control siRNA, and transfection reagent was also transfected cells and set as negative control group and blank group, respectively. After transfection, S100A4 transcription level of cells was determined by qRT-PCR, the expression levels of S100A4 and PKC/p53 pathway associated proteins were determined by Western-blot; cells ‘cisplatin sensitivity and cells’ invasion ability were analyzed by MTT method and Transwell assay and the cell cycle and apoptosis was determined by flow cytometry. Results: S100A4 expression level of cisplatinsensitive patients was lower than cisplatin-resistant patients; after transfection, IC₅₀ of blank group, negative control group and experimental group was 75.96, 66.73 and 40.31 μmol/L, respectively; the cells’ percentage in G1 phase of experimental group was higher than other groups while in S phase it was lower than other groups (p < 0.05); the expression level of PKC-δ/ε and p-p53 increased significantly (p < 0.05). Conclusions: Silencing S100A4 gene in CP70 cells could u-regulate the expression of PKC-δ/ε and p-p53, thus promoting apoptosis by PKC-δ/ε in coordination with p-p53 and increasing chemosensitivity of cells.