For this to be effective, however, providers need a screening and assessment approach that is efficient and accurate. Though very brief screening tools have been developed for this purpose, they typically don’t provide enough information about the specific substances used, or the patient’s risk level, to guide clinical actions. This study, CTN-0059, aimed to develop a better instrument for substance use screening in primary care settings. The resultant Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS) tool consists of a 4-item screen for tobacco, alcohol, illicit drugs, and nonmedical use of prescription medications, followed by a substance-specific assessment of risk level for individuals with positive screening results. The tool is flexible enough to be administered face-to-face or self-administered with a tablet computer, making it potentially useful in a variety of settings. The study involved comparing the TAPS tool to a reference standard measure, the World Mental Health Composite International Diagnostic Interview (CIDI), which measures problem use and substance use disorder (SUD). It was conducted at 5 adult primary care clinics with 2000 adult patients recruited from clinic waiting areas. Results found that interviewer- and self-administered versions of the TAPS tool had similar diagnostic characteristics. The tool had the highest sensitivity (correctly identifying those with SUD) and specificity (correctly identifying those without SUD) for problem substance use. Sensitivity and specificity were lower for tobacco, alcohol, and marijuana, so more refinement is needed before the TAPS tool can be recommended broadly for all SUD screening. Conclusions: Having information about a patient’s substance use is essential for ensuring the quality and safety of medical care. This study supports the use of the TAPS tool in screening diverse populations of adult primary care patients for problem substance use. Because it asks a limited number of questions to identify problem use of all commonly used substances and has the flexibility to be either self-administered or completed as an interview, the TAPS tool has the potential to ease barriers to incorporating substance use screening into busy clinical environments.