Background: In recent years, the historic declines in the incidence of methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSIs) in the United States have slowed. We examined trends in the incidence of community-onset (CO) MRSA BSIs among hospitalized persons with and without substance-use diagnoses. Methods: Using data from >200 US hospitals reporting to the Premier Healthcare Database (PHD) during 2012–2017, we conducted a retrospective study among hospitalized persons aged ≥18 years. MRSA BSIs with substance use were defined as hospitalizations having both a blood culture positive for MRSA and at least 1 International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) or ICD-10-CM diagnostic code for substance use including opioids, cocaine, amphetamines, or other substances (excluding cannabis, alcohol, and nicotine). MRSA BSIs were considered community onset when a positive blood culture was collected within 3 days of admission. We assessed annual trends and described characteristics of CO MRSA BSI hospitalizations, stratified by substance use. Results: Of 20,049 MRSA BSIs from 2012 to 2017, 17,634 (88%) were CO. Overall, MRSA BSI incidence decreased 7%, from 178.5 to 166.2 per 100,000 hospitalizations during the study period; However, CO MRSA BSI rates remained stable (152.7 to 149.9 per 100,000 hospitalizations). Among CO MRSA BSIs, 1,838 (10%) were BSIs with substance-use diagnoses; the incidence of CO MRSA BSIs with substance use increased 236% (from 8.2 to 27.6 per 100,000 hospitalizations) and represented a greater proportion of the CO MRSA rate over the study period (Fig. 1). The incidence of CO MRSA BSIs without substance use decreased 15% (from 144.5 to 122.4 per 100,000 hospitalizations). Patients with CO MRSA BSIs with substance use were younger (median, 40 vs 65 years), more likely to be female (50% vs 40%), white (79% vs 69%), and to leave against medical advice (15% vs 1%). Among patients not leaving against medical advice, CO BSI patients with substance-use diagnoses had longer lengths of stay (median, 11 vs 9 days), lower in-hospital mortality (9% vs 14%), and higher hospitalization costs (median, $22,912 vs $17,468) compared to patients without substance-use diagnoses. Conclusions: Although the overall CO MRSA BSI rate remained unchanged from 2012 to 2017, infections with substance use diagnoses increased >3-fold, and infections without substance use diagnoses decreased. These data suggest that the emergence of MRSA associated with substance-use diagnoses threatens potential progress in reducing the incidence of CO MRSA infections. Additional strategies may be needed to prevent MRSA BSI in patients with substance-use diagnoses, and to maintain national progress in the reduction of MRSA infections overall.