Safe injection self-efficacy (SISE) is negatively associated with injection risk behaviors among people who inject drugs (PWID) but has not been examined in differing risk environments. We compared responses to a validated SISE scale between PWID in San Diego, California and Tijuana, Mexico, and examine correlates of SISE among PWID in Tijuana. PWID were recruited via street outreach for a longitudinal cohort study from October 2020 – September 2021. We compared SISE scale items by city. Due to low variability in SISE scores among San Diego residents, we restricted analysis of factors associated with SISE to Tijuana residents and identified correlates of SISE score levels (low, medium, high) using ordinal logistic regression. Of 474 participants, mostwere male (74%), Latinx (78%) and Tijuana residents (73%). Mean age was 44. MeanSISE scores among San Diego residents were high (3.46 of 4 maximum) relative toTijuana residents (mean: 1.93). Among Tijuana residents, White race and havingpreviously resided in San Diego were associated with higher SISE scores. HCV andHIV seropositivity, homelessness, fentanyl use, polysubstance co-injection, and greaterinjection frequency were associated with lower SISE scores. We found profoundinequalities between Tijuana and San Diego SISE, likely attributable to differential riskenvironments. Associations with fentanyl and polysubstance co-injection, injectionfrequency, and both HIV and HCV seropositivity suggest that SISE contribute to bloodborne infection transmission risks in Tijuana. SISE reflects an actionable intervention target to reduce injection risk behaviors, but structural interventions are required to change the risk environment.