Background: Harm reduction (HR) interventions are essential to reduce human immunodeficiency virus (HIV) and hepatitis C virus (HCV) transmission in people who inject drugs (PWID). Preliminary testing of the Individually Tailored Support and Education for Safer Injection (ITSESI) evidence-based educational intervention for PWID was performed in France in 2011. We created the Eurosider project to implement and evaluate ITSESI at a wider European level, with a view to its future pan-European diffusion. Methods: We performed a mixed-methods study involving quantitative (a 6-month before-after study with PWID) and qualitative (focus groups with field workers) components. The study was conducted in 2018-2019 with 307 eligible PWID participating in four existing HR programmes in Bulgaria, Greece, Portugal, and Romania. ITSESI consists in trained field workers observing PWID injection practices and providing an educational exchange. For the present study, PWID participants were allocated to either the control group (i.e., they continued receiving only the current HR services) or the intervention group (i.e., current HR services plus ITSESI). We used the RE-AIM QuEST framework to assess the effectiveness of ITSESI and its acceptability by field workers. Effectiveness was defined as a reduction in both syringe sharing - the highest HIV/HCV transmission risk practice - and in cutaneous abscesses. We used a multivariable mixed logit model to analyse both effectiveness outcomes and to provide adjusted odds ratios (aOR) and 95% confidence intervals (CI). Field workers' acceptability of the intervention was described using a thematic analysis of the qualitative data. Results: Of the 307 PWID, 55% received ITSESI. Syringe sharing and cutaneous abscesses decreased during follow-up in the intervention group (from 25 to 16% and from 27 to 14%, respectively). Reductions were smaller in the control group (from 29 to 24% and from 23 to 18%, respectively). The multivariable analyses confirmed the effect of the intervention on both of these outcomes (aOR [95% CI]: 0.38 [0.17, 0.85]) and (aOR [95% CI]: 0.38 [0.16, 0.90], respectively). Our qualitative data on acceptability showed the feasibility of involving field workers as proactive research partners in making ITSESI more accessible and acceptable across Europe. Conclusions: We demonstrated both the effectiveness of ITSESI in reducing syringe sharing and cutaneous abscesses in four European countries, and a high level of intervention acceptability by field workers. Our findings provide important insights into how ITSESI can be adapted for pan-European implementation.