Purpose <p>To evaluate the clinical significance of PSMA-PET/CT-detected mesorectal lymph node metastases in biochemically recurrent prostate cancer patients.</p> Methods <p>This is a retrospective analysis of biochemically recurrent prostate cancer patients (post-radical prostatectomy and/or radiotherapy) with a positive ¹⁸F-DCFPyL-PSMA-PET/CT, performed at a tertiary center (December 2018– February 2021). We evaluated the association between site of most advanced disease (mesorectal-only versus other sites) and development of castration resistance using a multivariable Cox model. We additionally assessed prostate-specific antigen decrease by 50% [PSA50] and hormone-free survival in mesorectal nodal disease patients treated with metastasis-directed therapy.</p> Results <p>The cohort included 301 patients with PSMA PET-positive disease, of whom 71 had mesorectal nodal disease (44 had mesorectal-only disease). At a median follow-up of 36 months, patients with mesorectal nodal-only disease had equivalent rates of castration resistance development, compared to patients with prostatic fossa-limited disease (HR = 0.99, <i>p</i> = 0.88). Sixteen patients with mesorectal nodal disease underwent metastasis-directed therapy. A PSA50 response was observed in 5/10 patients with mesorectal nodal-only disease and 2/6 for those with additional pelvic nodal disease. All patients without a PSA50 response were started on hormones, with no castrate-resistance development to date. The median hormone-free survival was 28 months.</p> Conclusions <p>Biochemically recurrent patients with PSMA PET-detected mesorectal nodal disease have rates of castration-resistance development identical to those with prostatic fossa-limited disease and have promising clinical responses with metastasis-directed therapy. This suggests that such patients may potentially be spared upfront hormones and be considered for either surveillance or metastasis-directed therapy, in select circumstances.</p>