Background Rising midlife mortality in the United States (US) has raised concerns, particularly the increase in "deaths of despair" (due to drugs, alcohol, and suicide). While life expectancy is also stalling in other countries such as the UK, whether midlife mortality is rising outside the US is not known. Methods We document trends in midlife mortality in the US, UK and a group of 16 high-income countries in Western Europe, Australia, Canada, New Zealand, and Japan, as well as 7 Central and Eastern European (CEE) countries from 1990-2019. We use annual mortality data from the World Health Organization Mortality Database to analyze sex and age-specific (25-44, 45-54, and 55-64) age-standardized death rates across 13 major cause-of-death categories. Findings US midlife mortality rates worsened since 1990 for several causes of death including drug-related, alcohol-related, suicide, metabolic disease, nervous system disease, respiratory disease, and infectious/parasitic diseases. Deaths due to homicide, transport accidents, and cardiovascular disease declined overall since 1990 but saw recent increases or stalling of improvements. Midlife mortality has also recently increased in the UK for 45-54-year-olds, and in Canada, Poland, and Sweden among 25-44-year-olds. Conclusion The US is increasingly falling behind not only high-income but also CEE countries heavily impacted by the post-Soviet mortality crisis of the 1990s. While levels of midlife mortality in the UK are substantially lower than in the US overall, there are signs that UK midlife mortality is worsening relative to the rest of Europe.