Research on the determinants of injection drug use behavior has traditionally concentrated on factors operating at the individual level. However, more recent studies have found that behaviors surrounding injection drug use are shaped, not only by individual-level characteristics, but also by the environment in which they occur. The risk environment paradigm, proposed by Rhodes and colleagues, describes how factors exogenous to the individual influence high-risk injection behavior and blood borne virus (BBV) transmission among people who inject drugs (PWID). To date, few elements of the risk environment have been evaluated as potential determinants of high-risk injection behavior. The purpose of this dissertation was to study the influence of two elements of the risk environment on unsafe injection practices among PWID – neighborhood socioeconomic disadvantage and social discomfort surrounding the acquisition of sterile syringes from syringe exchange programs (SEPs) and pharmacies. To this end, a systematic literature review was conducted on the relation between neighborhood context and injection drug use behavior. Research gaps and methodological challenges identified in this review were used to design analyses exploring relations among neighborhood disadvantage, social discomfort, and high-risk injection behavior. These analyses were conducted using data collected from 484 PWID enrolled in the Pharmacists as Resources Making Links to Community Services (PHARM-Link) study, combined with data from the American Community Survey. Poisson regression with robust error variance was used to estimate associations between measures of neighborhood socioeconomic disadvantage and high-risk injection behavior. SEP accessibility and drug-related police activity were evaluated as potential modifiers of these relations. Similar methods were used to estimate associations between measures of social discomfort and high-risk injection behavior, including neighborhood socioeconomic disadvantage as a potential effect modifier. The systematic literature review on neighborhood context and injection drug use behavior identified few articles pertaining to this relation (n=22). Selected studies primarily investigated the influence of structural aspects of the neighborhood environment on behaviors surrounding injection drug use, while aspects of the social environment and potential modifiers of neighborhood-behavior relations were understudied. Subsequent quantitative analyses revealed that neighborhood socioeconomic disadvantage was associated with safer injection behaviors among PWID. Injectors in disadvantaged neighborhoods reported less receptive syringe sharing and less unsterile syringe use than their counterparts in relatively better off neighborhoods. Drug-related police activity attenuated associations between neighborhood disadvantage and unsterile syringe use, while the direction of associations between neighborhood disadvantage and the use of unsafe syringe sources varied with levels of SEP accessibility. In neighborhoods with high SEP accessibility, neighborhood disadvantage was associated with decreased use of unsafe syringe sources, while in neighborhoods with low SEP accessibility, neighborhood disadvantage was associated with increased use of unsafe syringe sources. Social discomfort was not associated with high-risk injection behavior, but effect modification was detected between neighborhood disadvantage and two items measuring the quality of relationships between participants and syringe staff: “Pharmacists care about my health and well-being” and “The staff at syringe exchange programs seems to care about my health and well-being.” In disadvantaged neighborhoods, participants who reported positive relationships with syringe staff were less likely to engage in receptive syringe sharing. However, in relatively better off neighborhoods, positive relationships with syringe staff were associated with increased receptive syringe sharing. Overall, the results of this dissertation support the validity of the risk environment paradigm in shaping high-risk injection behavior among PWID. Future studies should continue to investigate contextual factors as determinants of behavior surrounding injection drug use. Understanding how aspects of local-area environments influence injection risk behavior will be essential to eliminating the transmission of BBVs among PWID.