General medical hospitals provide care for a disproportionate share of patients who misuse substances. Hospitalization provides a unique opportunity to identify and motivate patients to address their substance misuse. To determine the effectiveness of three strategies for implementing motivational interviewing for substance misuse with general medical inpatients. Type 3 hybrid effectiveness-implementation randomized controlled trial (Clinical Trials.gov: NCT01825057). Thirty-eight providers (physicians, physician assistants, nurses) from 13 general medical inpatient services, and 1173 of their patients admitted to an academically affiliated acute care hospital. Implementation strategies included (1) a continuing medical education workshop on detection of substance misuse and provision of a motivational interview; (2) workshop plus bedside supervision (apprenticeship condition); and (3) a workshop plus ability to place a medical order for an interview from a consultation-liaison service (consult condition). Primary outcomes were the percentage of study-eligible patients who received an interview for substance misuse and the integrity (adherence, competence) of the interviews. The secondary outcome was the percent of patient statements within the interviews that indicated motivation for reducing substance misuse. 20.5% of patients in the consult condition received an interview, compared to 0.8% (Hedge's g = 1.49) and 3.0% (Hedge's g = 1.26) in the respective workshop only and apprenticeship conditions (p < 0.001). Motivational interviews in the consult condition were performed with more fundamental motivational interviewing adherence and competence than the other conditions. Most statements made by patients during the interviews favored reducing substance misuse, with no differences between conditions. Providers' ability to place an order to have experts from the consultation-liaison service deliver a motivational interview was a more effective implementation strategy than a workshop or apprenticeship method for ensuring motivational interviewing is available to medical inpatients who misuse substances. NCT01825057.