Abstract Background General medical hospitals provide care for a disproportionate share of patients who abuse or are dependent upon substances. This group is among the most costly to treat and has the poorest medical and addiction recovery outcomes. Hospitalization provides a unique opportunity to identify and motivate patients to address their substance use problems in that patients are accessible, have time for an intervention, and are often admitted for complications related to substance use that renders hospitalization a “teachable moment.” Methods/Design This randomized controlled trial will examine the effectiveness of three different strategies for integrating motivational interviewing (MI) into the practice of providers working within a general medical inpatient hospitalist service: (1) a continuing medical education workshop that provides background and “shows” providers how to conduct MI (See One); (2) an apprenticeship model involving workshop training plus live supervision of bedside practice (Do One); and (3) ordering MI from the psychiatry consultation-liaison (CL) service after learning about it in a workshop (Order One). Thirty providers (physicians, physician assistants, nurses) will be randomized to conditions and then assessed for their provision of MI to 40 study-eligible inpatients. The primary aims of the study are to assess (1) the utilization of MI in each condition; (2) the integrity of MI when providers use it on the medical units; and (3) the relative costs and cost-effectiveness of the three different implementation strategies. Discussion If implementation of Do One and Order One is successful, the field will have two alternative strategies for supporting medical providers’ proficient use of brief behavioral interventions, such as MI, for medical inpatients who use substances problematically. Trial registration Clinical Trials.gov ( NCT01825057 )