Here,　we　report　the　anti-human　immunodeficiency　virus　(HIV)　potency　and　underlying　mechanisms　of　a　Keggin　polyoxometalate　(PT-1,　K6HPTi2W10O40).　Our　findings　showed　that　PT-1　exhibited　highly　potent　effects　against　a　diverse　group　of　HIV　type　1　(HIV-1)　strains　and　displayed　low　cytotoxicity　and　genotoxicity.　The　time-addition　assay　revealed　that　PT-1　acted　at　an　early　stage　of　infection,　and　these　findings　were　supported　by　the　observation　that　PT-1　had　more　potency　against　Env-pseudotyped　virus　than　vesicular　stomatitis　virus　glycoprotein　(VSVG)　pseudotyped　virus.　Surface　plasmon　resonance　binding　assays　and　flow　cytometry　analysis　showed　that　PT-1　blocked　the　gp120　binding　site　in　the　CD4　receptor.　Moreover,　PT-1　bound　directly　to　gp41　NHR　(N36　peptide),　thereby　interrupting　the　core　bundle　formation　of　gp41.　In　conclusion,　our　data　suggested　that　PT-1　may　be　developed　as　a　new　anti-HIV-1　agent　through　its　effects　on　entry　inhibition.