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In 1999, the Centers for Disease Control and Prevention launched the National Plan to Eliminate Syphilis. From 1999 to 2003 in San Francisco, early syphilis was epidemic, increasing from 44 cases to 522 cases a year. Syphilis cases were more likely to be in gay or bisexual men, those with human immunodeficiency virus (HIV) infection, those who had anonymous partners, and those who met sex partners on the Internet. Increases in sexual activity and sexual risk behavior in men who have sex with men during this period have been attributed to the improved physical health of HIV-infected men on highly active antiretroviral therapy, HIV treatment optimism, increases in methamphetamine use, and the use of Viagra.The San Francisco Department of Public Health’s response to the epidemic included enhanced surveillance, expanded clinical and testing services, provider and community mobilization and sexual health education, and risk factor identification and abatement through investigations, public health advocacy, and treatment. Collaborations with community-based organizations and local businesses were key to the successful implementation of disease-control efforts. A multitude of converging risk factors and new environments contributed to the syphilis epidemic, requiring a comprehensive, innovative, and flexible disease-control strategy.