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Background: Substance use disorders, depression and anxiety disproportionately affect people with HIV (PWH) and lead to increased morbidity and mortality. Routine screening can help address these problems but is underutilized. This study sought to describe patient and provider perspectives on the acceptability and usefulness of systematic electronic, self-administered screening for tobacco, alcohol, other substance use, and mental health symptoms among patients in HIV primary care. Methods: Screening used validated instruments delivered pre-appointment by both secure messaging and clinic-based tablets, with results integrated into the electronic health record (EHR). Qualitative analysis of semi-structured interviews with 9 HIV primary care providers and 12 patients in the 3 largest HIV primary care clinics in the Kaiser Permanente Northern California health system who participated in a clinical trial evaluating computerized screening and behavioral interventions was conducted. Interviews were audio-recorded and transcribed. A thematic approach was utilized for coding and analysis of interview data using a combination of deductive and inductive methods. Results: Four key themes were identified: (1) perceived clinical benefit of systematic, electronic screening and EHR integration for providers and patients; (2) usefulness of having multiple methods of questionnaire completion; (3) importance of the patient–provider relationship to facilitate completion and accurate reporting; and (4) barriers, include privacy and confidentiality concerns about reporting sensitive information, particularly about substance use, and potential burden from repeated screenings. Conclusions: Findings suggest that electronic, self-administered substance use and mental health screening is acceptable to patients and may have clinical utility to providers. While offering different methods of screening completion can capture a wider range of patients, a strong patient–provider relationship is a key factor in overcoming barriers and ensuring accurate patient responses. Further investigation into facilitators, barriers, and utility of electronic screening for PWH and other high-priority patient populations is indicated.