Statement of Problem: Alkyl nitrites (poppers) are potent short-acting inhalants commonly used by men who have sex with men (MSM). Despite their association with HIV risk, their causal association and mechanism for HIV transmission is not well understood. The aims of this dissertation are to describe available literature on popper use in the U.S. in the context of HIV, identify research gaps, contribute to a better understanding of biological impacts of popper use on MSM with HIV, qualitatively describe contextual factors of popper use among young MSM with HIV, and provide recommendations for clinical care and future research. Methods: Chapter 1 - A scoping review on the use of poppers as a risk factor for people living with and at-risk for HIV in the U.S. was conducted using the Social Ecological Model to contextualize findings. Studies were included (N=89) if they reported results on non-clinical use of alkyl nitrites, were related to HIV or HIV risk, were published between 2001 and 2021, and were conducted in the U.S. Chapter 2 – Total HIV DNA from 90 stored peripheral blood mononuclear cells was measured. Non-parametric rank analysis of covariance (ANCOVA) was conducted on the dependent variable (HIV DNA), with group (popper use versus no popper use) as the independent variable and alcohol, tobacco, and cannabis use as covariates. Chapter 3 – In- depth, semi-structured interviews with 15 young MSM (18-30 years old) living with HIV were conducted to explore individual, social and environmental contexts of popper use influencing HIV care outcomes. Summary of Findings: Between 36% to 72% of MSM in the U.S. report lifetime popper use. Existing research supports the relationship between popper use and HIV risk, however the impact of popper use on the HIV care continuum remains unknown. Concurrent use of poppers and other drugs is common. Among MSM who use poppers, perceived risk of use is low and education is needed and desired. Clinicians caring for MSM and people with HIV are well situated to assess and address popper use. Implications for clinical care, public health, policy, and future research are discussed.