Background 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. Methods PWID were recruited via street outreach for a longitudinal cohort study from October 2020 to 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 scores (low, medium, high) using ordinal logistic regression. Results Of 474 participants, most were male (74%), Latinx (78%) and Tijuana residents (73%). Mean age was 44. Mean SISE scores among San Diego residents were high (3.46 of 4 maximum) relative to Tijuana residents (mean: 1.93). Among Tijuana residents, White race and having previously resided in San Diego were associated with higher SISE scores. HCV and HIV seropositivity, homelessness, fentanyl use, polysubstance co-injection, and greater injection frequency were associated with lower SISE scores. Conclusions We found profound inequalities between Tijuana and San Diego SISE, likely attributable to differential risk environments. Associations with fentanyl and polysubstance co-injection, injection frequency, and both HIV and HCV seropositivity suggest that SISE contribute to blood-borne infection transmission risks in Tijuana. SISE reflects an actionable intervention target to reduce injection risk behaviors, but structural interventions are required to intervene upon the risk environment.