During 2013-2017, the national annual rate of reported primary and secondary (P&S) syphilis cases in the United States increased 72.7%, from 5.5 to 9.5 cases per 100,000 population (1). The highest rates of P&S syphilis are seen among gay, bisexual, and other men who have sex with men (collectively referred to as MSM) (2), and MSM continued to account for the majority of cases in 2017 (1). However, during 2013-2017, the P&S syphilis rate among women increased 155.6% (from 0.9 to 2.3 cases per 100,000 women), and the rate among all men increased 65.7% (from 10.2 to 16.9 cases per 100,000 men), indicating increasing transmission between men and women in addition to increasing transmission between men (1). To further understand these trends, CDC analyzed national P&S syphilis surveillance data for 2013-2017 and assessed the percentage of cases among women, men who have sex with women only (MSW), and MSM who reported drug-related risk behaviors during the past 12 months. Among women and MSW with P&S syphilis, reported use of methamphetamine, injection drugs, and heroin more than doubled during 2013-2017. In 2017, 16.6% of women with P&S syphilis used methamphetamine, 10.5% used injection drugs, and 5.8% used heroin during the preceding 12 months. Similar trends were seen among MSW, but not among MSM. These findings indicate that a substantial percentage of heterosexual syphilis transmission is occurring among persons who use these drugs, particularly methamphetamine. Collaboration between sexually transmitted disease (STD) control programs and partners that provide substance use disorder services will be important to address recent increases in heterosexual syphilis.