Transgender women are at high risk for HIV, substance abuse, and mental health problems. We describe a health promotion intervention program tailored to transgender women in San Francisco. The program creates a safe space for providing transgender-sensitive education about HIV risk reduction, substance abuse prevention, and general health promotion. Transgender health educators conduct workshops and make referrals to appropriate substance abuse treatment programs and other services in the community. Evaluation findings indicate that this community-tailored intervention may be an effective way to reach transgender women and reduce sexual risk behaviors, depression, and perceived barriers to substance abuse treatment.