Polymetallic　high-entropy　nanosulfide　with　controlled　morphology　can　provide　high　stability　and　sensitivity　for　photoelectrochemical　(PEC)　immunoassays　due　to　their　fascinating　cocktail　effect　and　highly　customizable　electrochemical　properties.　Most　currently　available　methods　require　extremely　high　temperatures　to　homogeneously　mix　the　different　components,　which　further　limits　their　large-scale　synthesis.　Herein,　a　high-entropy　nanosulfide　(ZnCdCuAgCo)xS　with　cocktail　effect　was　prepared　by　mild　cation　exchange　reactions.　Initially,　(ZnCdCuAgCo)xS　was　an　excellent　semiconductor　that　functioned　as　a　photovoltaic　material　to　be　loaded　on　the　electrode　surface　because　of　the　synergistic　effect　between　different　metals.　A　sandwich-type　immunoreaction　has　been　performed　in　96-well　microtiter　plate,　linking　with　the　detection　antibody　modified　with　glucose　oxidase-loaded　gold　nanoparticles.　In　the　presence　of　prostate-specific　antigen　(PSA),　enzymatically　produced　H2O2　consumed　electrons　on　the　conduction　band　of　(ZnCdCuAgCo)xS　to　generate　H2O,　leading　to　a　decrease　in　the　photocurrent　of　the　system.　The　PEC　immunoassay　based　on　(ZnCdCuAgCo)xS　displayed　high　sensitivity　for　PSA　with　a　linear　range　of　0.03–10　ng　mL−1　and　a　low　detection　limit　of　9.62　pg　mL−1.　More　importantly,　the　results　of　clinical　serum　specimens　obtained　by　this　PEC　immunoassay　are　in　great　agreement　with　those　of　the　enzyme-linked　immunosorbent　assay.　©　2024　Elsevier　B.V.