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Cox proportional hazard models and Recursive Partitioning and Amalgamation (RECPAM) tree\u2010regression were used to analyze data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In pCIS, female sex and a multifocal onset were risk factors for a second clinical attack (hazard ratio [HR], 95% confidence interval [CI]\u2009=\u20091.28, 1.06\u20131.55; 1.42, 1.10\u20131.84, respectively), whereas disease\u2010modifying drug (DMD) exposure reduced this risk (HR, 95% CI\u2009=\u20090.75, 0.60\u20130.95). After pediatric onset MS (POMS) diagnosis, age at onset younger than 15 years and DMD exposure decreased the risk of a first Expanded Disability Status Scale (EDSS)\u2010worsening event (HR, 95% CI\u2009=\u20090.59, 0.42\u20130.83; 0.75, 0.71\u20130.80, respectively), whereas the occurrence of relapse increased this risk (HR, 95% CI\u2009=\u20095.08, 3.46\u20137.46). An exploratory RECPAM analysis highlighted a significantly higher incidence of a first EDSS\u2010worsening event in patients with multifocal or isolated spinal cord or optic neuritis involvement at onset in comparison to those with an isolated supratentorial or brainstem syndrome. A Cox regression model including RECPAM classes confirmed DMD exposure as the most protective factor against EDSS\u2010worsening events and relapses as the most important risk factor for attaining EDSS worsening.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This work represents a step forward in identifying predictors of unfavorable course in pCIS and POMS and supports a protective effect of early DMD treatment in preventing MS development and disability accumulation in this population. 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