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Gender differences in drug use are fluid and strongly patterned by social and institutional forces. Since 1995, the United States has been experiencing an opioid epidemic of unprecedented magnitude, generating the potential for rapid changes in gender differences in health and mortality. However, the contemporary American drug overdose epidemic impacts on gender differences in mortality remain largely unexplored. This paper examines: 1) how gender differences in drug overdose mortality changed between 1990 and 2016; 2) the factors underlying these gender differences, including whether marital status patterns the likelihood of dying from drug overdose differentially by gender; and 3) the epidemic’s implications for gender differences in life expectancy. This study finds that gender differences in drug overdose mortality show a distinctive pattern: they narrowed (1995-2010) in the heyday of the astronomical rise in the prescription of opioid painkillers—which were prescribed to women at higher rates than men—and then widened (2010-2016) once illicit drugs like heroin and fentanyl became responsible for the bulk of drug overdose deaths. Overall, gender differences in drug overdose have widened substantially, increasing eightfold between 1990 and 2016. During this period, age profiles of drug overdose mortality, which were initially similar for men and women, also diverged. Drug overdose mortality became relatively more concentrated at younger ages for men and older ages for women. Drug overdose has increasing salience for gender differences in life expectancy, particularly at the prime adult ages (20-64), where it accounted for 15.6% of the gender gap in 2016. The associations between marital status and drug overdose mortality also differ substantially by gender. Marriage appears to be consistently beneficial for men, with never married men accounting for the greatest share of drug overdose deaths, whereas the associations between marital status and drug overdose mortality have been more dynamic for women.