Ductal adenocarcinoma of the prostate (DA) is relatively rare and highly co-existent with prostate adenocarcinoma (AC). This study aimed to investigate the distinctive genomic profiles of patients with DA compared to those without. Blood samples were obtained from 144 patients (36 with DA and 108 without DA) who were diagnosed from 2017 to 2023 at West China Hospital. We performed cell-free DNA sequencing to investigate the genomic differences between patients with DA [DA(+)] and those without [DA(-)], and explored the potential associations between their mutational status and prognosis. Pathogenic and likely pathogenic alterations were included for analysis. We identified that AR pathway [16/36 (44.4%) versus 24/108 (22.2%), p = 0.017] and WNT pathway [6/36 (16.7%) versus 5/108 (4.6%), p = 0.029] mutations were significantly enriched in DA(+) compared to DA(-) patients. Mutation of FOXA1, as a key component of the AR pathway, demonstrated markedly higher prevalence in the DA(+) over the DA(-) cohort [25% (9/36) versus 4.6% (5/108), p = 0.0012]. The DNA damage repair mutation rate and the homologous recombination repair deficiency scores appeared to be comparable between the DA(+) and DA(-) patients. In the metastatic population, DA was characterized by a higher speckle-type POZ protein (SPOP) mutation rate. TP53 mutation was associated with a deteriorating prognosis for both DA(+) and DA(-) patients in terms of castration-free survival. In conclusion, our findings provide further genomic insights into prostate cancer with ductal morphology and are instructive for the diagnosis and treatment of DA.© 2025 The Author(s). The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.