Objective: The objective of this study was to compare 2 interventions promoting condoms and vaginal microbicides to prevent sexually transmitted disease (STD). Study: Women (N = 427) attending an STD clinic were randomly assigned to 2 clinician-delivered interventions and followed up monthly to assess condom/microbicide use and incidence of gonorrhea, chlamydia, and syphilis. Results: During follow up, condom use rates were 69% (enhanced) and 49% (basic) and microbicide use rates were 44% and 29%, respectively. STD rates did not significantly differ between intervention groups. Perfect condom use (regardless of intervention arm) was associated with a 3-fold decrease in STD rates (relative risk [RR], 0.3; 95% confidence interval [CI], 0.1-0.8). Using a vaginal microbicide during ≥50% of the acts of intercourse was associated with reduced STD rates (RR, 0.5; 95% CI, 0.3-1.0) across intervention groups and condom use categories. Conclusions: The enhanced intervention increased use of condoms and vaginal microbicide; however, STD rates did not decrease because a protective effect was seen only among perfect barrier users, and the enhanced intervention only modestly increased perfect use. Copyright © 2005, American Sexually Transmitted Diseases Association. All rights reserved.