Introduction: Increasing mortality rates among midlife non-Hispanic whites have been identified but are not well understood. Methods: Vital statistics data were used in 2017 to examine to what extent increases in mortality rates and years of potential life lost among midlife non-Hispanic whites from 1999 to 2015 are correlated with increases in fatal overdoses and specific drug categories. Results: The mortality rate rose by 21.2 per 100,000 people and years of potential life lost by 712,000 years from 1999 to 2015 for non-Hispanic whites aged 22-56 years; 63% of the mortality rate and 76% of the years of potential life lost increase occurred among individuals aged 22-39 years. For males, 92% of the mortality rate and 98% of the years of potential life lost growth was among individuals aged 22-39 years. The increases attributed to drug poisonings were: 26.4 per 100,000 people and 854,000 years, 51% and 64% of which occurred among individuals aged 22-39 years. Illicit opioids without involvement of prescription opioids were involved in mortality rate and years of potential life lost increases of 13.9 (95% CI=13.2, 14.7) per 100,000 people and 489,000 (95% CI=463,000, 515,000) years. For prescription opioids without illicit opioid involvement, the growth was 7.8 (95% CI=7.3, 8.3) per 100,000 people and 230,000 (95% CI=214,000, 246,000) years. Illicit opioids played a key role for individuals aged 22-39 years, especially males. Mortality rate and years of potential life lost declined dramatically for nonwhites or Hispanics aged 22-56 years, with only small increases because of drug deaths. Conclusions: Growth in fatal overdoses was strongly correlated with increased mortality rate and years of potential life lost for midlife non-Hispanic whites from 1999 to 2015, with a particularly large rise for young adults, especially males, and illicit opioids contributing most to this association. (C) 2018 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.