Solid　solutions　are　ubiquitous　in　metals　and　alloys.　Local　chemical　ordering　(LCO)　is　a　fundamental　sub-nano/nanoscale　process　that　occurs　in　many　solid　solutions　and　can　be　used　as　a　microstructure　to　optimize　strength　and　ductility.　However,　the　formation　of　LCO　has　not　been　fully　elucidated,　let　alone　how　to　provide　efficient　routes　for　designing　LCO　to　achieve　synergistic　effects　on　both　superb　strength　and　ductility.　Herein,　we　propose　the　formation　and　control　of　LCO　in　negative　enthalpy　alloys.　With　engineering　negative　enthalpy　in　solid　solutions,　genetic　LCO　components　are　formed　in　negative　enthalpy　refractory　high-entropy　alloys　(RHEAs).　In　contrast　to　conventional　‘trial-and-error’　approaches,　the　control　of　LCO　by　using　engineering　negative　enthalpy　in　RHEAs　is　instructive　and　results　in　superior　strength　(1160　MPa)　and　uniform　ductility　(24.5%)　under　tension　at　ambient　temperature,　which　are　among　the　best　reported　so　far.　LCO　can　promote　dislocation　cross-slip,　enhancing　the　interaction　between　dislocations　and　their　accumulation　at　large　tensile　strains;　sustainable　strain　hardening　can　thereby　be　attained　to　ensure　high　ductility　of　the　alloy.　This　work　paves　the　way　for　new　research　fields　on　negative　enthalpy　solid　solutions　and　alloys　for　the　synergy　of　strength　and　ductility　as　well　as　new　functions.　©　The　Author(s)　2024.