Objective To analyze the expression levels of E3 ubiquitin ligase HECW1 and CUB domain-containing protein 1 (CDCP1) in prostate cancer and their relationship with progression-free survival (PFS).Methods The clinical data of 86 patients with prostate cancer admitted to the 904th Hospital of the Joint Logistic Support Force of the Chinese People's Liberation Army during November 2020 to October 2024 were retrospectively analyzed. The relative mRNA and protein expression levels of HECW1 and CDCP1 in cancer and adjacent tissues were measured using quantitative real-time polymerase chain reaction and Western blotting, respectively. The relative mRNA and protein expression levels of HECW1 and CDCP1 in cancer tissues were compared between patients with different clinicopathological characteristics. Patients were followed up until October 2024, and PFS was recorded. Factors influencing PFS in prostate cancer patients were analyzed, and the predictive value of HECW1 and CDCP1 for PFS was assessed.Results The relative mRNA and protein expression levels of HECW1 and CDCP1 in cancer tissues were significantly higher than those in adjacent tissues (P < 0.05). There were no statistically significant differences in the relative mRNA and protein expression levels of HECW1 and CDCP1 in tumor tissues among patients of different ages or AAPR groups (P > 0.05). However, patients with PSA levels of 4-10 μg/L and > 10 μg/L had significantly higher relative mRNA and protein expression levels of HECW1 and CDCP1 in tumor tissues compared to those with PSA <4 μg/L (P < 0.05), and their expression levels in the >10 μg/L group were significantly higher than those in the 4-10 μg/L group (P < 0.05). Patients with Gleason scores of 7 and > 7 had significantly higher HECW1 and CDCP1 mRNA and protein expression than those with Gleason scores < 7 (P < 0.05), and expression was higher in the >7 group than in the 7 group (P < 0.05). Higher expression levels of HECW1 and CDCP1 were also observed in patients with TNM stage III/IV, lymph node metastasis, or bone metastasis (P < 0.05). As of October 2024, the median PFS among the 86 patients was 26 months (95% CI: 24.613, 27.387). Multivariable Logistic regression analysis demonstrated that high mRNA expression of HECW1 [O^R = 7.441 (95% CI: 2.543, 21.770) ], high protein expression of HECW1 [O^R = 5.355 (95% CI: 1.830, 15.667) ], high mRNA expression of CDCP1 [O^R = 4.477 (95% CI: 1.530, 13.099) ] and high protein expression of CDCP1 [O^R = 3.374 (95% CI: 1.153, 9.870) ] in cancer tissues were risk factors for PFS in patients with prostate cancer (P < 0.05). The ROC curve analysis revealed that the areas under the curves (AUCs) of the mRNA and protein expression levels of HECW1 and CDCP1 in cancer tissues for predicting PFS of prostate cancer patients were 0.846, 0.824, 0.857, and 0.805, with sensitivities of 85.8%, 83.4%, 90.0%, and 88.6%, and sensitivities of 87.1%, 89.3%, 80.6%, and 84.5%. The combination of the four yielded an AUC of 0.964, with the sensitivity being 98.4% and the specificity being 71.0%.Conclusion The increased mRNA and protein expressions of HECW1 and CDCP1 in patients with prostate cancer are related to PSA levels, Gleason scores, TNM stage, and lymph node and bone metastases. Moreover, their higher expression levels are associated with shorter PFS.