Background: Reducing substance use and unprotected sex by HIV-positive persons improves individual health status while decreasing the risk of HIV transmission. Despite recommendations that health care provides screen and counsel their HIV-positive patients for ongoing behavioral risks, it is unknown how to besr provide "prevention with positives" in clinical settings. Pasitive Choice, an interactive, patient-tailored computer program, was developed in the United States to improve clinic-based assessment and counseling for risky behaviors. Methodology and Findings: We conducted a parallel groups randomized controlled trial (December 2003-September 2006) at 5 San Francisco area outpatient HIV clinics. Eligible patients (HIV-positive English-speaking adults) completed an indepth computerized risk assessment. Participants reporting substance use or sexual risks (n = 476) were randomized in stratified blocks. The intervention group received tailored risk-reduction counseling from a "Video Doctor" via laptop computer and a printed Educational Worksheet; providers received a Cueing Sheet on reported risks. Compared with control, fewer intervention participants reported continuing illicit drug use (RR 0.81, 95% CI: 0.957, p=0.014 at 3 months; and RR 0.65, 95% CI: 0.540, 0.785, p<0.001 at 6 months) and unprotected sex (RR 0.88, 95% CI: 0.773, 0.993, p=0.039 at 3 months, and RR 0.80, 95% CI: 0.686, 0.941, p=0.007 at 6 months). Intervention participants reported fewer mean days of ongoing illicit drug use (-4.0 days vs. -1.3 days, p=0.346, at 3 months; and -4.7 days vs. -0.7 days, p=0.130,at 6 months) than did controls, and had fewer casual sex partners at (-2.3 vs. -1.4, p=0.461, at 3 months; and -2.7 vs. -0.6, p=0.042, at 6 months). Conclusions: The Positive Choice Intervention achieved significant cessation of illicit drug use and unprotected sex at the group-level, and modest individual-level reductions in days of ongoing drug use and number of casual sex partners compared with the control group. Positive Choice, including Video Doctor counseling, is an efficatious and appropriate adjunct to risk-reduction efforts in outpatient settings, and holds promise as a public health HIV intervention. © 2008 Gilbert et al.