Background <p>The unpredictable and toxic nature of the unregulated drug supply poses overdose and other health risks for people who use drugs (PWUD). Drug checking services can reduce risks by identifying adulterants in individuals’ drug supplies. In the United States (U.S.), DCS are increasingly offered through community harm reduction services that provide evidence-based risk reduction services for PWUD, such as syringe services programs (SSPs). However, PWUD face several multi-level barriers to consistently utilizing DCS and engaging in post-DCS safer drug use behaviors (e.g., discard, use less, avoid using alone, etc.). Staff from a San Diego-based mobile SSP and researchers drew from Social Cognitive Theory and the Social Ecological Model to develop a motivational-interviewing adjunctive intervention (MI-CHANCE) led by peers with lived substance use experience to address multi-level barriers and promote DCS engagement and adoption of post-DCS safer drug use behaviors among PWUD.</p> Methods <p>We employ a hybrid type-1 effectiveness–implementation trial with a primary goal of determining effectiveness of the MI-CHANCE adjunctive intervention in increasing DCS utilization (primary behavioral outcome) and safer drug use behaviors (secondary behavioral outcome), leading to reduced overdose risk (primary health outcome) and HIV/HCV incidence (secondary health outcome). We will recruit, consent, conduct a baseline interview, and randomize 588 PWUD who used opioids or stimulants within the week prior to receive either MI-CHANCE or an attention-control standard-of-care condition. All participants will be offered DCS following exposure to the intervention or control condition. We will conduct six-month follow-up with participants over a 30-month period to collect outcomes and hypothesized predictors, mediators and potential confounders. Our secondary goal is to assess MI-CHANCE implementation considerations guided by the RE-AIM/PRISM framework via annual in-depth interviews over the course of the trial with SSP staff (<i>N</i> = 5) and participants (<i>N</i> = 20), focusing on acceptability and feasibility, and the potential for scalability via interviews with a broad sample of diverse U.S. SSPs (<i>N</i> = 20).</p> Discussion <p>This hybrid trial will advance crucial knowledge on the effectiveness and implementation of an adjunctive intervention to promote DCS engagement and safer drug use behaviors to reduce overdose risk among PWUD.</p> Trial registration <p>ClinicalTrials.gov, NCT06855836. Registered February 28, 2025. <a href="https://clinicaltrials.gov/study/NCT06855836?term=NCT06855836/rank=1">https://clinicaltrials.gov/study/NCT06855836?term=NCT06855836/rank=1</a>.</p>