Background: Peripartum depression (PPD) is underexplored in multiple sclerosis (MS). Objective: To evaluate prevalence of and risk factors for PPD in women with MS. Methods: Retrospective single-center analysis of women with MS with a live birth. Prevalence of PPD was estimated with logistic regression with generalized estimating equations (GEE). GEE evaluated predictors of PPD (e.g. age, marital status, parity, pre-pregnancy depression/anxiety, antidepressant discontinuation, sleep disturbance, breastfeeding, relapses, gadolinium-enhancing lesions, and disability). Factors significant in univariable analyses were included in multivariable analysis. Results: We identified 143 live births in 111 women (mean age 33.1 ± 4.7 years). PPD was found in 18/143 pregnancies (12.6%, 95% CI = 7.3–17.8). Factors associated with PPD included older age (OR 1.16, 95% CI = 1.03–1.32 for 1-year increase), primiparity (OR 4.02, CI = 1.14–14.23), pre-pregnancy depression (OR 3.70, CI = 1.27–10.01), sleep disturbance (OR 3.23, CI = 1.17–8.91), and breastfeeding difficulty (OR 3.58, CI = 1.27–10.08). Maternal age (OR 1.17, CI = 1.02–1.34), primiparity (OR 8.10, CI = 1.38–47.40), and pre-pregnancy depression (OR 3.89, CI = 1.04–14.60) remained significant in multivariable analyses. Relapses, MRI activity, and disability were not associated with PPD. Conclusion: The prevalence of PPD in MS appeared similar to the general population, but was likely underestimated due to lack of screening. PPD can affect MS self-management and offspring development, and prospective studies are needed.