Background and purpose: Sex differences in multiple sclerosis (MS) prevalence and disease course are thought to be driven by hormones. Exogenous exposure to estrogens may affect MS disease course. Thus, our aim was to investigate the association between hormone therapy (HT) and disease activity and disability accrual among women with MS. Methods: A register-based cohort study was conducted with prospectively enrolled cases from the Danish MS registry. Information on hormone exposure was retrieved from the National Prescription Registry. Outcomes were relapse rate, relapse rate ratio, recurrent relapses, 6-month confirmed and sustained Expanded Disability Status Scale (EDSS) milestones 4 and 6, and recurrent EDSS worsening. Results: In all, 3325 women were eligible for analyses, of whom 333 (10%) were ever on HT at some time during follow-up. We found no association between HT and disability accrual, although a trend for increasing risk with increasing length of use was seen. The risk of reaching 6-month confirmed and sustained EDSS 4 among users was 0.6 (95% confidence interval [CI] = 0.3–1.2) after <1 year of use and 1.4 (95% CI = 0.9–2.2) after >5 years of HT compared to never use. The risk of recurrent relapse was increased by 20% (95% CI = 1.0–1.4) among current users of HT compared to nonusers. However, the risk of recurrent relapses was driven by the first calendar period (1996–2005) before the introduction of high-efficacy disease-modifying therapy. Conclusions: Our findings from this nationwide MS population suggest that HT does not affect disability accrual in women with MS, especially if used for <5 years.