Midlife increases in suicides and drug poisonings have been previously noted. However, that these upward trends were persistent and large enough to drive up all-cause midlife mortality has, to our knowledge, been overlooked. If the white mortality rate for ages 45-54 had held at their 1998 value, 96,000 deaths would have been avoided from 1999-2013, 7,000 in 2013 alone. If it had continued to decline at its previous (1979-1998) rate, half a million deaths would have been avoided in the period 1999-2013, comparable to lives lost in the US AIDS epidemic through mid-2015. Concurrent declines in self-reported health, mental health, and ability to work, increased reports of pain, and deteriorating measures of liver function all point to increasing midlife distress.