ABSTRACT The endgame for eliminating HIV will become increasingly difficult as transmission persists in populations who are the most marginalized from society, the hardest to reach with prevention programs, and the most challenging to include in epidemiological studies. Although San Francisco appears on track to achieve zero new HIV infections within the next few years, the trajectory among people who inject drugs (PWID) lags behind. The slower rate of decrease in HIV among PWID may be due to lower levels of awareness and uptake of pre-exposure prophylaxis (PrEP). Meanwhile, neighboring Alameda County (home to Oakland) has seen little decrease in the HIV epidemic, and outbreaks occur among PWID who are Black/African American or experiencing homelessness. In addition to HIV, PWID in the US are experiencing a surge in deaths due opioid overdose. To end the HIV epidemic and mitigate other health disparities for PWID, data collection systems need to be more rapid, representative, and responsive to this population at high risk. We therefore propose to create a new epidemiological data collection system for PWID in Alameda and San Francisco counties called Brief Longitudinal Incident Sentinel Surveillance (BLISS). We will recruit 600 PWID (300 each in county) using a novel venue-based / peer-referral hybrid method called Starfish Sampling to accrue a cohort and follow them longitudinally. Following HIV testing and a baseline questionnaire, participants will be enlisted to provide monthly brief responses to 11 sentinel events of high significance to the HIV and substance use epidemics (e.g., PrEP uptake or discontinuation, harm reduction program utilization, overdose experiences). Monthly data will be collected through smart phone and online technologies with in-person options as back up. Selected sentinel events will trigger “deeper dive” data collection through ecological momentary assessments (EMAs). The sample size is geared to detect events occurring at low rates in the community as early warning signals and to obtain sufficient longitudinal data to assess causal factors for HIV risk and preventive behaviors, particularly barriers and facilitators to PrEP use and adherence. BLISS data will help identify and avert outbreaks, micro-target interventions, prioritize those at highest risk, fill unmet care and prevention needs, and end the HIV epidemic.