Background:　Neuroblastoma　(NB)　is　the　most　common　extracranial　solid　tumor　in　children,　with　high-risk　NB　(HR-NB)　exhibiting　dismal　survival　rates　due　to　aggressive　biology　and　therapy　resistance.　E2F　transcription　factors　(E2Fs)　are　pivotal　regulators　of　cell　cycle　progression　and　immune　modulation,　yet　their　prognostic　and　therapeutic　implications　in　NB　remain　underexplored.　Methods:　Using　transcriptomic　data　from　the　GEO,　TARGET,　and　E-MTAB-8248　cohorts,　we　identified　E2F-associated　molecular　subtypes　via　consensus　clustering.　A　prognostic　signature　was　constructed　via　LASSO　regression　and　validated　for　risk　stratification.　Immune　infiltration,　tumor　mutation　burden　(TMB),　and　drug　sensitivity　were　analyzed　via　the　CIBERSORT,　ESTIMATE,　and　GDSC　databases.　Results:　Four　E2F-related　genes　(MAD2L1,　CDC25A,　CKS2,　and　NME1)　were　used　to　construct　a　prognostic　nomogram　that　stratified　patients　into　high-　and　low-risk　groups,　with　low-risk　patients　exhibiting　superior　overall　survival　(P　＜　0.05).　Multivariate　Cox　regression　confirmed　that　the　model　was　an　independent　prognostic　factor　(P　＜　0.001).　High-risk　patients　presented　lower　immune　and　stromal　scores,　reduced　immune　checkpoint　expression,　distinct　immune　cell　infiltration　patterns,　and　significant　differences　in　mutation　spectrum　and　drug　sensitivity　(P　＜　0.001).　Conclusions:　The　E2F-related　prognostic　signature　effectively　stratifies　NB　patients　by　risk　and　provides　potential　biomarkers　for　prognosis　and　targeted　therapy　in　HR-NB　patients.　The　identified　signature　enhances　patient　stratification　and　provides　insights　into　NB　tumor　biology,　the　immune　landscape,　and　potential　treatment　strategies.