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Prostate cancer (PCa) is a heterogeneous and prevalent neoplasm, traditionally stratified by PSA and Gleason Score. However, these biomarkers have prognostic limitations, driving the search for new molecular markers. Alterations in DNA mismatch repair (MMR) system proteins are associated with genomic instability, therapeutic resistance, and poorer clinical outcomes. Their relevance in PCa remains poorly understood, highlighting MMR status as a potential prognostic biomarker. This systematic review, following PRISMA 2020 guidelines, evaluated the relationship between MMR protein (MSH2, MSH6, MLH1, PMS2) expression and clinical-pathological outcomes in PCa. Ten studies assessing MMR protein expression in prostate adenocarcinoma samples were included. Risk of bias was assessed using the Newcastle-Ottawa Scale. Studies revealed heterogeneous MMR protein expression. Loss of MSH2 consistently correlated with poorer clinical outcomes, including biochemical recurrence, higher Gleason Scores, and perineural invasion. MSH6 was more prevalent in high-grade tumors, without clear prognostic association. Cytoplasmic MLH1 expression was linked to aggressive histological patterns; PMS2 results were conflicting. Two studies assessed Microsatellite Instability (MSI), correlating with MSH2 and PMS2. Overall, MMR protein alterations, particularly MSH2 loss, may indicate worse PCa prognosis. However, methodological heterogeneity and lack of standardization hinder definitive conclusions. Further studies, integrating MSI analyses are crucial to confirm their prognostic.