Background Experts recommend that treatment for substance use disorder (SUD) be integrated into primary care. The Digital Therapeutics for Opioids and Other SUD (DIGITS) Trial tests strategies for implementing reSET (R) and reSET-O (R), which are prescription digital therapeutics for SUD and opioid use disorder, respectively, that include the community reinforcement approach, contingency management, and fluency training to reinforce concept mastery. This purpose of this trial is to test whether two implementation strategies improve implementation success (Aim 1) and achieve better population-level cost effectiveness (Aim 2) over a standard implementation approach.Methods/Design The DIGITS Trial is a hybrid type III cluster-randomized trial. It examines outcomes of implementation strategies, rather than studying clinical outcomes of a digital therapeutic. It includes 22 primary care clinics from a healthcare system in Washington State and patients with unhealthy substance use who visit clinics during an active implementation period (up to one year). Primary care clinics implemented reSET and reSET-O using a multifaceted implementation strategy previously used by clinical leaders to roll-out smartphone apps ( standard implementation including discrete strategies such as clinician training, electronic health record tools). Clinics were randomized as 21 sites in a 2x2 factorial design to receive up to two added implementation strategies: (1) practice facilitation, and/or (2) health coaching. Outcome data are derived from electronic health records and logs of digital therapeutic usage. Aim 1's primary outcomes include reach of the digital therapeutics to patients and fidelity of patients' use of the digital therapeutics to clinical recommendations. Substance use and engagement in SUD care are additional outcomes. In Aim 2, population-level cost effectiveness analysis will inform the economic benefit of the implementation strategies compared to standard implementation. Implementation is monitored using formative evaluation, and sustainment will be studied for up to one year using qualitative and quantitative research methods.Discussion The DIGITS Trial uses an experimental design to test whether implementation strategies increase and improve the delivery of digital therapeutics for SUDs when embedded in a large healthcare system. It will provide data on the potential benefits and cost-effectiveness of alternative implementation strategies. Identifier: NCT05160233 (Submitted 12/3/2021).