The drug epidemic in the United States continues to evolve. The drug overdose death rate has rapidly increased among women (1,2), although within this demographic group, the increase in overdose death risk is not uniform. From 1999 to 2010, the largest percentage changes in the rates of overall drug overdose deaths were among women in the age groups 45-54 years and 55-64 years (1); however, this finding does not take into account trends in specific drugs or consider changes in age group distributions in drug-specific overdose death rates. To target prevention strategies to address the epidemic among women in these age groups, CDC examined overdose death rates among women aged 30-64 years during 1999-2017, overall and by drug subcategories (antidepressants, benzodiazepines, cocaine, heroin, prescription opioids, and synthetic opioids, excluding methadone). Age distribution changes in drug-specific overdose death rates were calculated. Among women aged 30-64 years, the unadjusted drug overdose death rate increased 260%, from 6.7 deaths per 100,000 population (4,314 total drug overdose deaths) in 1999 to 24.3 (18,110) in 2017. The number and rate of deaths involving antidepressants, benzodiazepines, cocaine, heroin, and synthetic opioids each increased during this period. Prescription opioid-related deaths increased between 1999 and 2017 among women aged 30-64 years, with the largest increases among those aged 55-64 years. Interventions to address the rise in drug overdose deaths include implementing the CDC Guideline for Prescribing Opioids for Chronic Pain (3), reviewing records of controlled substance prescribing (e.g., prescription drug monitoring programs, health insurance programs), and developing capacity of drug use disorder treatments and linkage to care, especially for middle-aged women with drug use disorders.