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Safe consumption spaces (SCS) are evidence-based interventions that reduce drug-related morbidity and mortality operating in many countries. However, SCS are yet to be widely implemented in the USA despite the escalating overdose epidemic. The aim of this multi-city study was to identify the factors associated with willingness to use a SCS among people who use drugs (PWUD) in Baltimore, Providence, and Boston, stratified by injection drug use status. Our secondary aim was to characterize the anticipated barriers to accessing SCS if they were to be implemented in these cities. PWUD were invited to complete a cross-sectional survey in 2017. The analysis was restricted to 326 opioid users (i.e., heroin, fentanyl, and non-medical opioid pill use). The majority (77%) of participants expressed willingness to use a SCS (Baltimore, 78%; Providence, 68%; Boston. 84%). Most respondents were male (59%), older than 35 years (76%), non-white (64%), relied on public/semi-public settings to inject (60%), had a history of overdose (64%), and recently suspected fentanyl contamination of their drugs (73%). A quarter (26%) preferred drugs containing fentanyl. Among injectors, female gender, racial minority status, suspicion of drugs containing fentanyl, and drug use in public/semi-public settings were associated with higher willingness to use a SCS; prior arrest was associated with lower willingness. Among non-injectors, racial minority status, preference for fentanyl, and drug use in public/semi-public settings were associated with higher willingness, whereas recent overdose held a negative association. The most commonly anticipated barriers to accessing a SCS in the future were concerns around arrest (38%), privacy (34%), confidentiality/trust/safety (25%), and cost/time/transportation (16%). These data provide evidence of high SCS acceptability among high-risk PWUD in the USA, including those who prefer street fentanyl. As SCS are implemented in the USA, targeted engagement efforts may be required to reach individuals exposed to the criminal justice system. [ABSTRACT FROM AUTHOR]