Purpose:　Cerebrospinal　fluid　(CSF)　has　revealed　the　unique　genetic　characteristics　of　leptomeningeal　metastasis　(LM)　from　non-small　cell　lung　cancer　(NSCLC).　However,　the　research　in　this　area　is　still　very　limited.　Methods:　Patients　with　LM　from　NSCLC　(n　=　80)　were　retrospectively　analyzed.　Circulating　tumor　DNA　(ctDNA)　in　CSF　was　tested　by　next-generation　sequencing　(NGS),　with　paired　extracranial　tissue　or　plasma　samples　included　for　comparison.　An　independent　non-LM　cohort　(n　=　100)　was　also　analyzed　for　comparative　purposes.　Clinical　outcomes　were　compared　with　Kaplan–Meier　log-rank　test　and　Cox　proportional　hazards　methodologies.　Results:　An　overwhelming　93.8%　of　patients　carried　druggable　mutations　in　NSCLC　LM,　with　EGFR　(78.8%)　being　the　most　prevalent.　Notably,　4　patients　who　tested　negative　for　driver　genes　in　extracranial　samples　surprisingly　showed　EGFR　mutations　in　their　CSF　and　subsequently　benefited　from　targeted　therapy.　There　was　a　clear　difference　in　genetic　profiles　between　CSF　and　extracranial　samples,　with　CSF　showing　more　driver　gene　detections,　increased　Copy　Number　Variations　(CNVs),　and　varied　resistance　mechanisms　among　individuals.　Abnormalities　in　cell-cycle　regulatory　molecules　were　highly　enriched　in　LM　(50.9%　vs　31.0%,　p　=　0.017),　and　CDKN2A/2B　deletions　were　identified　as　an　independent　poor　prognostic　factor　for　LM　patients,　with　a　significant　reduction　in　median　OS　(p　=　0.013),　supported　by　multivariate　analysis　(HR　2.63,　95%　CI　1.32–5.26,　p　=　0.006).　Conclusions:　CSF-based　ctDNA　analysis　is　crucial　for　detecting　and　characterizing　genetic　alterations　in　NSCLC　LM.　The　distinct　genetic　profiles　in　CSF　and　extracranial　tissues　emphasize　the　need　for　personalized　treatment　approaches.　©　2023,　The　Author(s),　under　exclusive　licence　to　Springer　Science+Business　Media,　LLC,　part　of　Springer　Nature.