Importance Most women with multiple sclerosis (MS) will experience menopause while living with MS. Despite this, the impact of menopause on MS disease trajectory remains unclear. Objective To assess whether menopause modifies the risk of disability progression for women with relapse-onset MS. Design, Setting, and Participants This retrospective cohort study used prospective clinical data that were collected within the MSBase Registry. Data were extracted from MSBase on July 1, 2023. These data were analyzed from January 2023 through February 2025. Female participants were recruited from 8 Australian neuroimmunology specialist centers (1 private practice and 7 tertiary referral centers) from 2018 through 2021. Participants included 1468 women aged 18 years or older who completed dedicated retrospective women’s health surveys. Of these, 987 women with relapse-onset MS, 3 or more Expanded Disability Status Scale (EDSS) measurements recorded, and reported menopausal status were included in the primary analysis. The secondary analysis included 209 women with 1 or more EDSS measurements recorded in the MSBase database predate and postdate of menopause onset. Exposure Crude and adjusted Cox proportional hazards models were used to assess the impact of menopause, modeled as a time-varying covariate, on progressive disability milestones. Analyses were adjusted for age at MS onset, baseline disease duration, baseline EDSS score, baseline relapse, and exposure to high-efficacy disease-modifying therapy modeled as a time-varying covariate. Main Outcome Measures In the primary analysis, the main outcome was time to 6-month confirmed disability progression (CDP). The secondary outcome was time to secondary progressive MS (SPMS). The secondary inflection point analysis examined longitudinal changes in EDSS in women who were followed up with throughout their menopausal transition. Results Primary analysis included 583 premenopausal and 404 postmenopausal women with MS. The median age at menopause was 48.5 years. Following multivariable adjustment, menopause was not associated with an increased risk of CDP or SPMS (hazard ratio, 0.95; 95% CI, 0.70-1.29; P = .70 and hazard ratio, 1.00; 95% CI, 0.60-1.67; P = 1.00), respectively. In the secondary analysis, menopause did not represent an inflection point in EDSS worsening following multivariable adjustment. Conclusions and Relevance While reproductive aging may be additive to the effects of somatic aging, these results do not support menopause as the leading factor for disability progression in older women with MS.