PURPOSE Pathologists diagnose prostate cancer (PCa) on hematoxylin and eosin (HE)–stained sections of prostate needle biopsies (PBx). Some laboratories use costly immunohistochemistry (IHC) for all cases to optimize workflow, often exceeding reimbursement for the full specimen. Despite the rise in digital pathology and artificial intelligence (AI) algorithms, clinical implementation studies are scarce. This prospective clinical trial evaluated whether an AI-assisted workflow for detecting PCa in PBx reduces IHC use while maintaining diagnostic safety standards. METHODS Patients suspected of PCa were allocated biweekly to either a control or intervention arm. In the control arm, pathologists assessed whole-slide images (WSI) of PBx using HE and IHC stainings. In the intervention arm, pathologists used the Paige Prostate Detect AI algorithm on HE slides, requesting IHC only as needed. IHC was requested for all morphologically negative slides in the AI arm. The main outcome was the relative risk (RR) of IHC use per detected PCa case at both patient and WSI levels. RESULTS Overall, 143 of 237 (60.3%) slides of 64 of 82 patients contained PCa (78.0%). AI assistance significantly reduced the risk of IHC use per detected PCa case at both the patient level (RR, 0.55; 95% CI, 0.39 to 0.72) and slide level (RR, 0.41; 95% CI, 0.29 to 0.52). Cost reductions on IHC were €1,700 for the trial, at €50 per IHC stain. AI-assisted pathologists reported higher confidence in their diagnoses (80% v 56% confident or high confidence). The median assessment time per HE slide showed no significant difference between the AI-assisted and control arms (139 seconds v 112 seconds; P = .2). CONCLUSION This study demonstrates that AI assistance for PCa detection in PBx significantly reduces IHC costs while maintaining diagnostic safety standards, supporting the business case for AI implementation in PCa detection.