The　effect　of　combined　antibiotics　exposure　on　nitrogen　removal,　microbial　community　assembly　and　proliferation　of　antibiotics　resistance　genes　(ARGs)　is　a　hotspot　in　activated　sludge　system.　However,　it　is　unclear　that　how　the　historical　antibiotic　stress　affects　the　subsequent　responses　of　microbes　and　ARGs　to　combined　antibiotics.　In　this　study,　the　effects　of　combined　sulfamethoxazole　(SMX)　and　trimethoprim　(TMP)　pollution　on　activated　sludge　under　legacy　of　SMX　or　TMP　stress　with　different　doses　(0.005-30　mg/L)　were　investigated　to　clarify　antibiotic　legacy　effects.　Nitrification　activity　was　inhibited　under　higher　level　of　combined　exposure　but　a　high　total　nitrogen　removal　(∼70%)　occurred.　Based　on　the　full-scale　classification,　the　legacy　effect　of　past　antibiotic　stress　had　a　marked　effect　on　community　composition　of　conditionally　abundant　taxa　(CAT)　and　conditionally　rare　or　abundant　taxa　(CRAT).　Rare　taxa　(RT)　were　the　keystone　taxa　in　the　microbial　network,　and　the　responses　of　hub　genera　were　also　affected　by　the　legacy　of　antibiotic　stress.　Nitrifying　bacteria　and　genes　were　inhibited　by　the　antibiotics　and　aerobic　denitrifying　bacteria　(Pseudomonas,　Thaurea　and　Hydrogenophaga)　were　enriched　under　legacy　of　high　dose,　as　were　the　key　denitrifying　genes　(napA,　nirK　and　norB).　Furthermore,　the　occurrences　and　co-selection　relationship　of　94　ARGs　were　affected　by　legacy　effect.　While,　some　shared　hosts　(eg.,　Citrobacter)　and　hub　ARGs　(eg.,　mdtD,　mdtE　and　acrD)　were　identified.　Overall,　antibiotic　legacy　could　affect　responses　of　activated　sludge　to　combined　antibiotic　and　the　legacy　effect　was　stronger　at　higher　exposure　levels.　©　2022