We aimed to establish a novel epithelial-mesenchymal transition (EMT)-related gene prognostic index (EMTGPI) associated with biochemical recurrence (BCR) and drug resistance for prostate cancer (PCa).We used Lasso and Cox regression analysis to establish the EMTGPI. All analyses were conducted with R version 3.6.3 and its suitable packages.We established the EMTGPI based on SFRP4 and SPP1. Patients in high-risk group had 2.23 times of BCR risk than those in low-risk group (p = 0.003), as well as 2.36 times of metastasis risk (p = 0.053). In external validation, we detected similar diagnostic efficacy and prognostic value in terms of BCR free survival. For drug resistance, we observe moderately diagnostic accuracy of EMTGPI score (AUC: 0.804). We found that PDCD1LG2 (p = 0.04) and CD96 (p = 0.01) expressed higher in BCR patients compared with their counterpart. For TME analysis, we detected that CD8+ T cells and M1 macrophages expressed higher in BCR group. Moreover, stromal score (p = 0.003), immune score (p = 0.01), and estimate score (p = 0.003) were higher in BCR patients. We found that EMTGPI was significantly related to HAVCR2 (r: 0.34), CD96 (r: 0.26), CD47 (r: 0.22), KIR3DL1 (r: -0.21), KLRD1 (r: -0.21), and CD2 (r: 0.21). In addition, we observed that EMTGPI was significantly associated with M1 macrophages (r: 0.6), M2 macrophages (r: -0.33), monocytes (r: -0.18), neutrophils (r: -0.43), CD8+ T cells (r: 0.13), and dendritic cells (r: 0.37). PHA-793887 was the common drug sensitive to SPP1 and SFRP4, and PC3 and DU145 were the common PCa-related cell lines of SPP1, SFRP4, and PHA-793887.We concluded that the EMTGPI score based on SFRP4 and SPP1 could be used to predict BCR for PCa patients. We confirmed the impact of immune evasion on the BCR process of PCa.Copyright © 2022 Feng, Shi, Xiong, Zhang, Li and Yang.