OBJECTIVE: To determine whether basing the decision to initiate immediate vs delayed disease-modifying therapy (DMT) on extent of recovery after initial relapse affects long-term disability accumulation in a multiple sclerosis (MS) evidence-based setting. METHODS: We analyzed the double-blind, placebo-controlled interferon beta-1a 30 mc once a week in clinically isolated syndrome and 10-year-follow-up extension trial. Good recovery after presenting relapse was defined as (1) full early recovery within 28 days of symptom onset (Expanded Disability Status Scale [EDSS] score of 0 at enrollment maintained >/=6 months) and (2) delayed good recovery (EDSS score > 0 at enrollment and improvement from peak deficit to 6th-month or 1-year visit >/= median). Time from recovery assignment to future disability (EDSS score >/= 2.5 or >/=4.0) was studied on a relapse-recovery-stratified age axis and immediate vs 3-year delayed treatment initiation with Kaplan-Meier statistics and hazard ratios (HRs). RESULTS: One hundred seventy-five/328 patients had good recovery (94 immediate and 81 delayed treatment); 153 did not have good recovery (77 immediate and 76 delayed treatment). HRs for EDSS score >/=2.5 outcome were: delayed treatment without good recovery as reference (HR = 1.0), delayed treatment with good recovery (HR(6th-month): 0.67, p = 0.207; HR(1st-year): 0.40, p = 0.027), immediate treatment without good recovery (HR(6th-month): 0.56, p = 0.061; HR(1st-year): 0.40, p = 0.011), and immediate treatment with good recovery (HR(6th-month): 0.43, p = 0.014; HR(1st-year): 0.48, p = 0.034). Placebo patients were switched to long-term treatment after 3 years, and insufficient EDSS score >/=4.0 outcome events were available to study. CONCLUSIONS: In patients with MS presenting without good recovery after the initial relapse, immediate DMT initiation favorably influences the likelihood of more ambulatory-benign disease akin to patients with good recovery after the initial relapse. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with MS without good recovery after the initial relapse, immediate DMT initiation increases the likelihood of a benign disease course.