Abstract It is difficult to underestimate the potential public health significance of the COVID-19 pandemic for generating new outbreaks of HIV among PWID. While public health scale implementation of “combined prevention and care for HIV” among PWID has led to dramatic reductions in HIV transmission in many high-income countries, multiple outbreaks of HIV have also occurred, e.g., in the US, Western and Eastern Europe, and Israel. While there were distinct features of each outbreak, a number of common features were noted across the outbreaks, including: 1) community economic dislocations, 2) inadequate or interrupted HIV prevention services, 3) local introduction of new injectable drugs, and 4) homeless PWID as a very high-risk group. The COVID-19 pandemic and its associated lockdown/control measures appear to be re-creating the very conditions that generated HIV outbreaks among PWID in the pre- COVID-19 era. The recent FDA emergency use authorization of effective SARS-CoV-2 vaccines provides a critical opportunity to alleviate some—but certainly not all—of the threats to HIV prevention. However, important potential difficulties in rapidly vaccinating large numbers of PWID exist. We propose to examine relationships between HIV, COVID-19, and racial/ethnic disparities among PWID in NYC, a location that has experienced the world’s largest local HIV epidemic among PWID, and one of the world’s largest local COVID-19 epidemics, through four specific aims: 1. Assess short term (within 3 years) impact of the COVID-19 pandemic on HIV risk among PWID in NYC, including potential increases in critical bio-behavioral risks (composite risk for HIV transmission and composite multi-person risk for HIV acquisition). 2. Monitor SARS-CoV-2 vaccination over time among PWID in NYC. Identify factors associated with receiving vaccination, including ‘underlying health conditions,” socio-demographics, particularly race/ethnicity and employment, vaccine awareness and attitudes, and across patterns of drug use. Examine peer, family and “trusted sources” influences on receiving vaccination. Educate participants on SARS-CoV-2 vaccines, including availability, types, side effects and scheduling. Assess the extent to which “herd immunity” is being achieved among PWID. 3. Utilize antibody testing to estimate past and incident COVID-19 infection among PWID, identifying risk factors for infection, including race/ethnicity, and whether practicing protective behaviors is associated with lower seroprevalence. 4. Using principal component analysis (PCA), examine relationships between multiple health problems and social determinants of health among PWID in NYC, including HIV, COVID-19, HCV, opioid and stimulant use, drug overdose, homelessness, and economic and food insecurity, during the COVID-19 pandemic. Examine patterns of racial/ethnic disparities among the clusters of health and social determinants of health.