Background: Despite pharmacologic therapy, people with multiple sclerosis (MS) often experience spasticity, which can worsen with longer disease duration and may contribute to disease progression. Long-term use of commonly prescribed treatments, such as baclofen, is associated with poor tolerability resulting in suboptimal dosing and limited therapeutic benefit. Arbaclofen, a g-aminobutyric acid-B (GABAB) receptor agonist, is the active R-enantiomer of racemic baclofen. Arbaclofen extended-release (ER) tablets provide for sustained concentrations of drug, allowing for twice-daily dosing. Objectives: To evaluate the long-term safety and tolerability of arbaclofen ER in patients with MS-related spasticity. Methods: In a 52-week, open-label, multicenter study, adults with a Total Numeric-Transformed Modified Ashworth Scale (TNmAS) score ?2 in the most-affected limb (MAL) received oral arbaclofen ER titrated over 9 days up to 80 mg/day. The primary objective was assessment of safety and tolerability. Secondary objectives were the assessment of efficacy using the TNmAS-MAL, the Patient Global Impression of Change (PGIC), and Expanded Disability Status Scale (EDSS). Results: Of 323 patients enrolled, 218 (67.5%) completed 1 year of treatment. Most patients who completed the study (74.0%) achieved an arbaclofen ER maintenance dose of 80 mg/day. At least one treatment-emergent adverse event (TEAE) was reported by 276 patients (85.4%). The most common TEAEs were (n patients [%]): urinary tract disorder (111 [34.4%]), muscular weakness (101 [31.3%]), nausea (66 [20.4%]), asthenia (61 [18.9%]), dizziness (51 [15.8%]), and somnolence (40 [12.4%]). The majority of TEAEs were of mild severity. Twenty-eight serious TEAEs were experienced by 21 patients. One death occurred due to a myocardial infarction considered unlikely to be related to study medication. Overall, 14.6% of patients discontinued due to TEAEs, primarily muscle weakness, MS relapse, asthenia, nausea, and gait disturbance. At Week 28, the overall mean (standard deviation) change from baseline in TNmAS-MAL score was 0.7 (1.73). PGIC scores 4 weeks after tapering from arbaclofen ER remained slightly reduced from baseline, while overall EDSS scores were maintained throughout the study. Conclusions: Twice-daily arbaclofen ER treatment (up to 80 mg/day) was well tolerated for up to 1 year. Clinically meaningful improvements in TNmAS-MAL scores suggested a long-term benefit for patients with MS-related spasticity.