KMT2 (lysine methyltransferase) family enzymes are epigenetic regulators that activate gene transcription. KMT2C is mainly involved in enhancer-associated H3K4me1, and is also one of the top mutated genes in cancer (6.6% in pan-cancer). Currently, the clinical significance of KMT2C mutations in prostate cancer is understudied.We included 221 prostate cancer patients diagnosed between 2014 and 2021 in West China Hospital of Sichuan University with cell-free DNA-based liquid biopsy test results in this study. We investigated the association between KMT2C mutations, other mutations, and pathways. Furthermore, we evaluated the prognostic value of KMT2C mutations, measured by overall survival (OS) and castration resistance-free survival (CRFS). Also, we explored the prognostic value of KMT2C mutations in different patient subgroups. Lastly, we investigated the predictive value of KMT2C mutations in individuals receiving conventional combined anti-androgen blockade (CAB) and abiraterone (ABI) as measured by PSA progression-free survival (PSA-PFS).The KMT2C mutation rate in this cohort is 7.24% (16/221). KMT2C-mutated patients showed worse survival than KMT2C-wild type (WT) patients regarding both CRFS and OS (CRFS: mutated: 9.9 vs. WT: 22.0 months, p = 0.015; OS: mutated: 71.9 vs. WT 137.4 months, p = 0.012). KMT2C mutations were also an independent risk factor in OS [hazard ratio: 3.815 (1.461, 9.96), p = 0.006] in multivariate analyses. Additionally, we explored the association of KMT2C mutations with other genes. This showed that KMT2C mutations were associated with Serine/Threonine-Protein Kinase 11 (STK11, p = 0.004) and Catenin Beta 1 (CTNNB1, p = 0.008) mutations. In the CAB treatment, KMT2C-mutated patients had a significantly shorter PSA-PFS compared to KMT2C-WT patients. (PSA-PFS: mutated: 9.9 vs. WT: 17.6 months, p = 0.014). Moreover, KMT2C mutations could effectively predict shorter PSA-PFS in 10 out of 23 subgroups and exhibited a strong trend in the remaining subgroups.KMT2C-mutated patients showed worse survival compared to KMT2C-WT patients in terms of both CRFS and OS, and KMT2C mutations were associated with STK11 and CTNNB1 mutations. Furthermore, KMT2C mutations indicated rapid progression during CAB therapy and could serve as a potential biomarker to predict therapeutic response in prostate cancer.© 2023 Zhu et al.