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To evaluate the efficacy of a cognitive/behavioral skills-building intervention to prevent sexually transmitted diseases (STD) in high-risk heterosexual adults.A randomized controlled trial with assessments at baseline, and at 3 and 5 months.San Francisco STD Clinic.A total of 399 patients were randomly assigned to a four-session, individual, multi-component, cognitive/behavioral intervention (n = 199), or a brief standardized counseling session offered to all patients (n = 200).Based on the AIDS Risk-Reduction Model, the aims of the intervention were to increase prevention knowledge, reduce high-risk psychosocial factors, and build decision-making and communication skills to modify sexual behaviors.The primary outcome of interest was STD. The secondary outcome was number of risky sexual activities.There were no differences between the intervention (13%) and control (11%) groups in their acquisition of STD. Among men, condom use increased more at 3 months in the intervention group than the control group (56.8 versus 42.3%; P< 0.05). In addition, the mean number of sexual partners without condom use was lower in the intervention group than in the control group at 5 months (0.6 versus 0.9; P< 0.01).The results suggest that a cognitive/behavioral, skills-building intervention consisting of individual, multiple sessions and follow-up assessments can be implemented and evaluated with high-risk heterosexually active adults attending public STD clinics. Our intervention did not have a significant impact on STD, although it had some impact on behavior in men, but not in women.