OBJECTIVE: To establish recommendations based on an expert consensus on the early and appropriate use of high-efficacy disease-modifying therapies (HE-DMTs) in the management of multiple sclerosis (MS) patients, based on current clinical evidence and real-world practice in Italy. MATERIAL AND METHODS: A Delphi panel comprising 65 neurologists from 54 Italian MS centers engaged in a two-round consensus process. Experts rated 43 statements across five domains: therapeutic goals, definitions of HE-DMT, MS patient profiling, and use of HE-DMT at diagnosis and later in MS course, using a 5-point Likert scale. A statement reached strong consensus if ≥80% of panelists agreed; whereas between 70% and 80% it was considered as moderate. RESULTS: In Round 2, 53 experts completed the survey on 43 statements. Strong consensus was achieved for 33 (76.7%), and moderate consensus for 6 (14.0%) statements. Experts strongly supported early HE-DMT initiation to prevent irreversible disability, endorsed a multidimensional definitions of treatment efficacy, and recommended personalized approaches based on clinical, radiological, and biomarker indicators. Consensus supported initiating HE-DMTs in patients with poor prognostic features and identified magnetic resonance imaging (MRI) activity, neurodegeneration markers, and suboptimal clinical response as specific factors requiring escalation to HE-DMTs. CONCLUSION: This Italian Delphi underscores the importance of early, personalized HE-DMT use to optimize long-term outcomes in MS. The strong expert alignment reflects a paradigm shift toward proactive treatment and highlights actionable clinical, radiological, and biological indicators that should guide therapeutic decisions. These findings may support national policy changes and promote more equitable and evidence-based access to HE-DMTs across healthcare systems.