Abstract Women with HIV remain underrepresented in research despite possessing a higher risk for the development and progression of HIV-associated comorbidities compared to men with HIV. Representing one of the major contributors to global years of life lost and the second most common comorbidity in people with HIV (PWH), obstructive lung disease (OLD) is an important health priority for PWH worldwide. OLD promises to increase in importance as the HIV population ages and as OLD risk factors such as smoking and biomass fuel exposure continue to collide with medical conditions such as tuberculosis. Women with HIV are particularly vulnerable to OLD; not only have HIV seronegative women demonstrated increased susceptibility for the development of OLD, but women with HIV have overall increased levels of immune activation markers, many of which have been linked to pulmonary dysfunction. However, whether sex-based differences in OLD exist among PWH has not been well characterized. To define sex-based differences in pulmonary dysfunction in PWH and to investigate sex-specific mechanisms in OLD risk, we propose a supplement to the NHLBI funded Inflammation, Aging, Microbes, Obstructive Lung Disease, and Diffusion Abnormalities (I AM OLD-DA) study. Under the current I AM OLD-DA study, we are performing serial pulmonary function tests to measure spirometry and diffusing capacity for carbon monoxide (DLco) over time as well as analyzing 12 inflammatory biomarkers in our established cohorts in San Francisco, California and Kampala, Uganda to better characterize HIV-associated pulmonary disease and to elucidate its underlying mechanisms. Thus far, we have found a distinct biomarker signature for pulmonary dysfunction in PWH. Further, in our pilot data analysis, we found over a four-fold increase in odds of OLD in women with HIV as compared to men with HIV, a disparity that was not seen between women and men without HIV, indicating a potential HIV-specific sex-based difference that has important implications for our understanding of OLD in persons with and without HIV. With this supplement, we will address whether there are sex-specific drivers for pulmonary dysfunction in our Ugandan cohort through the addition of sex hormones and sex-stratified biomarkers. This project would be the first of its kind in: (1) evaluating sex-based differences in spirometry and DLco in PWH in an international setting (Aim 1); (2) comparing spirometry and DLco to sex- stratified biomarkers (Aim 2); and (3) examining the role of sex and reproductive age on OLD through the measurement of sex hormones (Aim 3). This supplement proposal addresses three of the ORWH Strategic Goals (Strategic Goals 1, 2, and 4) through the addition of samples that focus on sex-based differences. Should there be a relationship between certain biomarkers, reproductive age, and OLD in women with HIV, this could provide key insights into underlying mechanisms in sex-based differences in pulmonary dysfunction...