BACKGROUND:Substance use is common among people living with HIV (PLHIV) and is associated with worse outcomes along the HIV care continuum. One potentially effective clinic-based approach to addressing unhealthy substance use is screening, brief intervention, and referral to treatment (SBIRT). METHODS:We conducted a two-arm randomized trial to examine the effects of a self-administered, computerized SBIRT intervention compared to a clinician-administered SBIRT intervention in an HIV primary clinic. Patients were surveyed before receiving the intervention and again at 1, 3, and 6 months. We administered the WHO Alcohol, Smoking and Substance Involvement Screening Test to determine Specific Substance Involvement Scores (SSIS) and to assign participants to categories of lower, moderate, or high risk to health and other problems for each substance. We collapsed moderate or severe risk responses into a single moderate-high risk category. Based on low rates of participation in the computerized arm, we conducted an "as treated" analysis to examine 6-month changes in mean SSIS among SBIRT intervention participants. RESULTS:For the overall sample (n = 208), baseline mean SSIS were in the moderate risk category for alcohol, tobacco, cannabis, cocaine, amphetamine, sedatives and opioids. Of those enrolled, 134 (64.4%) received the intervention, and 109 (52.4%) completed the 6-month follow up. There was a statistically significant decline in mean SSIS for all substances except tobacco and cannabis among participants who were at moderate-high risk at baseline. We also observed a statistically significant increase in mean SSIS for all substances except amphetamines and sedatives among participants who were at lower risk at baseline. CONCLUSIONS:Substance use among patients in this urban, safety-net, HIV primary care clinic was near universal, and moderate risk substance use was common. Among participants who received the SBIRT intervention, mean SSISs decreased among those at moderate-high risk at baseline, but increased among those at lower risk at baseline over the 6-month study period. Additional research should examine the clinical significance of SSIS changes for PLHIV, which SBIRT components drive changes in substance use scores, and what other interventions might support those patients at lower risk to maintain health and engagement along the HIV care continuum. Trial registration ClinicalTrials.gov study NCT01300806.