BACKGROUND: Syringe services programs (SSPs) reduce the risk of overdose by distributing supplies like naloxone. SSPs also support clients in meeting their basic needs via referrals to organizations providing food, housing, and healthcare. This paper describes the Exploration of Novel Harm Reduction Approaches to Increase Client Engagement (ENHANCE) Project, a prospective cohort study developed in partnership with people who use drugs that aims to characterize the influence of longitudinal engagement in SSPs on overdose risk behaviors. METHODS: The ENHANCE Project protocol was developed with a community leadership team of 16 people with living experience of drug use who were clients from four SSPs in Wisconsin that serve as study recruitment sites. The community leadership team met five times to conceptualize the study priorities, protocol, recruitment strategies, and measures. ENHANCE will enroll 400 people who use opioids and/or stimulants via recruitment of clients from study sites and peer referrals. Clients will report on primary outcomes (overdose experiences and risk behaviors) and other covariates (substance use history and behaviors, mental and physical health, satisfaction of basic needs, stigma, and others) over a 2-year follow-up period. At enrollment, clients select a self-generated identification code that is documented in all subsequent harm reduction services received from ten SSPs in Wisconsin. These data will be linked to study survey data using probabilistic methods and used for the primary exposure variable, frequency of using SSP services. ENHANCE will test the primary hypothesis that more frequently using SSP services is associated with reduced overdose risk behavior frequency. PRELIMINARY RESULTS: Among the first 125 clients enrolled, 22.4% (N = 28) reported personally experiencing an opioid overdose in the 6 months before enrollment and 38.4% (N = 48) experienced adverse effects after using stimulants. The most common overdose risk behaviors reported in the past 30 days were using opioids while alone (mean: 9.9 days [standard deviation: 10.7]) and injecting heroin (mean: 9.3 days [standard deviation: 12.8]). CONCLUSIONS: This study will identify aspects of harm reduction services that are most effective in reducing overdose risk to inform future service provision, funding, and policy efforts.