Background People who inject drugs may be at elevated SARS-CoV-2 risk due to their living conditions and/or exposures when seeking or using drugs. No study to date has reported upon risk factors for SARS-CoV-2 infection among people who inject drugs. Methods and findings Between October, 2020 and June, 2021, participants aged ≥18 years from San Diego, California, USA and Tijuana, Baja California, Mexico who injected drugs within the last month underwent interviews and testing for SARS-CoV-2 RNA and antibodies. Binomial regressions identified correlates of SARS-CoV-2 seropositivity. Results Of 386 participants, SARS-CoV-2 seroprevalence was 36.3% (95% CI: 31.5%-41.1%); 92.1% had detectable IgM antibodies. Only 37.5% had previously been tested. Seroprevalence did not differ by country of residence. None tested RNA-positive. Most (89.5%) reported engaging in ≥1 protective behavior [e.g., facemasks (73.5%), social distancing (46.5%), or increasing handwashing/sanitizers (22.8%)]. In a multivariate model controlling for sex, older age, and Hispanic/Latinx/Mexican ethnicity were independently associated with SARS-CoV-2 seropositivity, as was engaging in sex work (AdjRR: 1.63; 95% CI: 1.18–2.27) and having been incarcerated in the past six months (AdjRR: 1.49; 95% CI: 0.97–2.27). Comorbidities and substance using behaviors were not associated with SARS-CoV-2 seropositivity. Conclusions In this community-based study of people who inject drugs in the San Diego-Tijuana border region, over one third were SARS-CoV-2 seropositive, exceeding estimates from the general population in either city. We found no evidence that substance use behaviors were associated with an elevated risk of SARS-CoV-2 infection, but observed that circumstances in the risk environment, notably sex work and incarceration, were independently associated with higher SARS-CoV-2 seroprevalence. Our findings suggest that a binational policy response to COVID-19 mitigation is warranted beyond the closure of the U.S.-Mexico border. Furthermore, decriminalizing sex work and drug use could reduce the burden of COVID-19 among people who inject drugs.