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Background: Serine-arginine protein kinase 1 (SRPK1) has been implicated in prostate cancer (PCa) progression. However, its prognostic value and association with ERG and PTEN expression, two of the most common genetic alterations, have not been explored fully., Objective: We assessed the prognostic value of SRPK1 in association with ERG and PTEN in a cohort of patients managed nonsurgically by androgen deprivation therapy (ADT) for advanced disease., Design Setting and Participants: The study cohort consisted of men diagnosed with PCa by transurethral resection of the prostate (TURP; n  = 480). The patients were divided into three main groups: incidental (patients with Gleason score [GS] ≤7 with no prior ADT), advanced (patients with GS ≥8 with no prior ADT), and castrate-resistant PCa (patients with prior ADT)., Outcome Measurements and Statistical Analysis: A total of 480 TURP samples were assessed by immunohistochemistry for SRPK1, ERG, and PTEN, and results were correlated with Gleason grade group (GG), overall survival (OS), and PCa-specific mortality (PCSM)., Results and Limitations: High SRPK1 expression was noted in 105/455 (23%) available patient cores. Expression of SRPK1 was associated with Gleason grade grouping ( p  < 0.0001) with high expression detected in 22/74 (33%) with GG 5. High SRPK1 was not associated with ERG positivity ( p  = 0.18) but was significantly associated with PTEN intensity ( p  = 0.001). High SRPK1 was associated with OS (hazard ratio [HR] 1.99; confidence interval [CI]: 1.57-2.54, p  < 0.0001) and PCSM (HR 1.64; CI: 1.19-2.26, p  < 0.002). Adjusting for Gleason score, patients with high SRPK1 and negative PTEN had the worst clinical outcome for both OS and PCSM compared with other patients ( p  < 0.0001, HR: 3.02; CI: 1.87-4.88 and HR: 6.40, CI: 3.19-12.85, respectively)., Conclusions: High SRPK1 is associated with worse OS and PCSM. Moreover, patients with high SRPK1 expression and loss of PTEN had the worst clinical outcome for OS and cancer-specific mortality. Combined status of SRPK1 and PTEN may provide added value in stratifying patients into various prognostic groups., Patient Summary: The expression of serine-arginine protein kinase 1 (SRPK1) combined with PTEN has a significant prognostic role in prostate cancer patients. Patients with high SRPK1 expression and negative PTEN had the worst clinical outcome for overall survival and cancer-specific mortality., (© 2021 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.)