Antibiotic　resistance　genes　(ARGs)　are　widespread　in　aquatic　environments,　but　we　know　little　about　their　biogeographical　distribution　and　occurrence　at　national　scales.　Here　we　analyzed　the　patterns　of　ARGs　from　42　natural　waterbodies　(natural　lakes　and　reservoirs)　across　China　using　high-throughput　approaches.　The　major　ARGs　were　multidrug　genes　and　the　main　resistance　mechanism　was　the　efflux　pump.　Although　the　absolute　abundance　of　ARGs　(gene　copies/L)　in　the　south/central　waterbodies　was　similar　to　the　northern　waterbodies,　the　normalized　abundance　of　ARGs　(ARGs/16S　rRNA　gene　copy　number)　was　higher　in　the　south/central　waterbodies　than　in　the　north　(mainly　because　of　the　aminoglycoside　and　multidrug　resistance　genes).　Human　activities　strongly　correlated　with　the　normalized　abundance　of　ARGs.　The　composition　of　ARGs　in　the　waterbodies　of　south/central　China　was　different　from　that　in　the　north,　and　ARGs　showed　a　distance-decay　relationship.　Anthropogenic　factors　had　the　most　significant　effects　on　this　spatial　distribution　of　ARG　composition,　followed　by　the　spatial,　bacterial　and　physicochemical　factors.　These　indicate　that　the　ARGs　exhibited　biogeographical　patterns　and　that　multiple　ecological　mechanisms　-　such　as　environmental　selection　(human　activities　and　local　physicochemical　parameters)　and　dispersal　limitation　-　influence　distribution　of　ARGs　in　these　waters.　In　general,　our　results　provide　a　valuable　ecological　insight　to　explain　the　large-scale　dispersal　patterns　in　ARGs,　thereby　having　potential　applications　for　both　public　health　and　environmental　management.