Background: The 1-year placebo-controlled (PC) phase of the Glatiramer Acetate Low-Frequency Administration (GALA) study showed that glatiramer acetate 40 mg/mL three times weekly (GA40) significantly reduced annualized relapse rate (ARR) and magnetic resonance imaging (MRI) activity in patients with relapsing-remitting multiple sclerosis. Patients completing the PC phase were invited to an open-label (OL) extension. Objective: To evaluate the effects of early start (ES) and delayed start (DS) of GA40 over 3 years. Methods: A total of 97.2% of patients completing the PC phase received GA40 in the OL extension. ES (n=943) patients received GA40 throughout; DS (n=461) patients received placebo during the PC phase and GA40 during the OL phase. Relapse, MRI, disease progression, and safety were evaluated. Results: A total of 1041 patients completed 3 years of follow-up. During the OL phase, ES and DS patients showed comparable ARRs (0.20-0.22) and similar numbers of gadolinium-enhancing T1 (p=0.49) and new or enlarging T2 lesions (p=0.51) at Year 3. ES patients showed significantly smaller changes in gray matter volume than DS patients from Months 12 to 36 (mean difference, 0.371%; p=0.015), with similar trend in whole-brain volume (p=0.080). Adverse events were mild, consistent with the well-established glatiramer acetate (GA) safety profile. Conclusion: GA40 conferred treatment benefit over 3 years: sustained low ARR and lesion activity and favorable safety.