As life expectancy increases with effective combination antiretroviral therapy (ART), more women with HIV (WWH) are reaching menopause. WWH experience more frequent and severe vasomotor symptoms (VMS; the collective term for hot flashes and night sweats) than women without HIV. The menopausal transition is also associated with increasing risk of aging-related comorbidities such as osteoporosis/fracture, cardiovascular disease and neurocognitive impairment that disproportionately affect WWH. Menopausal hormone therapy (HT) is the most effective treatment for VMS; however, utilization is low and HT has never been studied in WWH. We propose a randomized, double-blind, placebo-controlled, 2x2 cross-over trial (n=80) to evaluate the efficacy of HT (transdermal estrogen plus oral progesterone) versus placebo for symptomatic peri- and early post-menopausal WWH with VMS (Aim 1). We will also compare the effects of HT versus placebo on neurocognitive function, mood, sleep and quality of life using a battery of assessments that have been studied specifically in WWH during menopause (Aim 2). HT has noted anti-inflammatory properties; therefore, we will evaluate the effect of HT on biomarkers of bone and cardiometabolic heath and examine the role of systemic inflammation (Aim 3). Lastly, we will measure effects of HT on the HIV reservoir using the Envelope Detection by Induced Transcription-based Sequencing (EDITS) assay, providing prospective experimental data to validate observational data findings of increased inducible HIV reservoir in WWH after menopause (Exploratory Aim). Our proposal leverages the resources and infrastructure of the AIDS Clinical Trials Group (ACTG). Eligibility criteria and endpoints have also been designed to align with MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health Trials) network trials to allow for future analyses comparing HT response in women with and without HIV. The results of our study will provide critical information about the role of HT in prevention of aging-related comorbidities and will elucidate whether systemic inflammation is a modifiable mechanistic pathway. Further, this trial will set the groundwork for future research comparing HT to non-hormonal therapies for treatment of VMS and prevention of comorbidities in aging WWH.