ABSTRACT Aims To determine the comparative levels of and associations between policing interference and characteristics of US syringe exchange programs (SEPs). Design Cross-sectional. Setting A national survey of US SEPs. Participants A total of 111 program managers (representing 59% of all US SEPs). Measurements Program manager self-report. Findings With overall interference profiles ranging from systematic to totally interference-free, 43% of respondents reported at least monthly client harassment, 31% at least monthly unauthorized confiscation of clients' syringes, 12% at least monthly client arrest en route to or from SEP and 26% uninvited police appearances at program sites at least every 6 months. In multivariate modeling, legal status of SEP, jurisdiction's syringe regulation environment and affiliation with health department were not associated with frequency of police interference. Programs serving predominantly injection drug users (IDUs) of color were 3.56 times more likely to report frequent client arrest en route to or from SEP and 3.92 times more likely to report unauthorized syringe confiscation. Those serving more than three sites were 3.96 times more likely to report client harassment, while stationary operation was protective against uninvited police appearances. The majority (56%) reported not documenting adverse police events; those who did were 2.92 times more likely to report unauthorized syringe confiscation from clients. Conclusions Findings highlight limitations of the impact of legal reforms on aligning police activities with SEP operations. Systematic adverse event surveillance and evidence-based structural interventions are needed to maximize the benefits of public health prevention targeting IDUs and other criminalized populations. SEPs that report no adverse events may represent programs already working in harmony with law enforcement agencies, a priority highlighted in US Centers for Disease Control's new SEP guidelines. The significance of mechanisms translating criminal justice disparities into health disparities is discussed.