INTRODUCTION: Injecting-related bacterial and fungal infections are a common complication among people who inject drugs (PWID), associated with significant morbidity and mortality. Invasive infections, including infective endocarditis, appear to be increasing in incidence. To date, preventive efforts have focused on modifying individual-level risk behaviours (eg, hand-washing and skin-cleaning) without much success in reducing the population-level impact of these infections. Learning from successes in HIV prevention, there may be great value in looking beyond individual-level risk behaviours to the social determinants of health. Specifically, the risk environment conceptual framework identifies how social, physical, economic and political environmental factors facilitate and constrain individual behaviour, and therefore influence health outcomes. Understanding the social and structural determinants of injecting-related bacterial and fungal infections could help to identify new targets for prevention efforts in the face of increasing incidence of severe disease. METHODS AND ANALYSIS: This is a protocol for a systematic review. We will review studies of PWID and investigate associations between risk factors (both individual-level and social/structural-level) and the incidence of hospitalisation or death due to injecting-related bacterial infections (skin and soft-tissue infections, bacteraemia, infective endocarditis, osteomyelitis, septic arthritis, epidural abscess and others). We will include quantitative, qualitative and mixed methods studies. Using directed content analysis, we will code risk factors for these infection-related outcomes according to their contributions to the risk environment in type (social, physical, economic or political) and level (microenvironmental or macroenvironmental). We will also code and present risk factors at each stage in the process of drug acquisition, preparation, injection, superficial infection care, severe infection care or hospitalisation, and outcomes after infection or hospital discharge. ETHICS AND DISSEMINATION: As an analysis of the published literature, no ethics approval is required. The findings will inform a research agenda to develop and implement social/structural interventions aimed at reducing the burden of disease. PROSPERO REGISTRATION NUMBER: CRD42021231411.