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BACKGROUND: Air quality across the northern hemisphere over the past two decades has witnessed dramatic changes, with continuous improvement in developed countries in North America and Europe, but a contrasting sharp deterioration in developing regions of Asia. OBJECTIVE: This study investigates the historical trend in the long-term exposure to PM[sub 2.5] and PM[sub 2.5]-related premature mortality (PM[sub 2.5]-mortality) and its response to changes in emission that occurred during 1990-2010 across the northern hemisphere. Implications for future trends in human exposure to air pollution in both developed and developing regions of the world are discussed. METHODS: We employed the integrated exposure-response model developed by Health Effects Institute to estimate the PM[sub 2.5]-mortality. The 1990-2010 annual average PM[sub 2.5] concentrations were obtained from the simulations using the WRF-CMAQ model. Emission mitigation efficiencies of sulfur dioxide (SO[sub 2]), nitrogen oxides (NO[sub x]), ammonia (NH3), and primary PM are estimated from the PM[sub 2.5]-mortality responses to the emission variations. RESULTS: Estimated PM[sub 2.5]-mortalities in East Asia and South Asia increased by 21% and 85% respectively, from 866,000 and 578,000 in 1990, to 1,048,000 and 1,068,000 in 2010. PM[sub 2.5]-mortalities in developed regions (i.e., Europe and high-income North America) decreased substantially by 67% and 58% respectively. CONCLUSIONS: Over the past two decades, correlations between population and PM[sub 2.5] have become weaker in Europe and North America due to air pollution controls but stronger in East Asia due to deteriorating air quality. Mitigation of primary PM appears to be the most efficient way for increasing health benefits (i.e., providing the largest mortality reduction per unit emissions). However, reductions in emissions of NH[sub 3] are needed to maximize the effectiveness of NO[sub x] emission controls. CITATION: Wang J, Xing J, Mathur R, Pleim JE, Wang S, Hogrefe C, Gan CM, Wong DC, Hao J. 2017. Historical trends in PM[sub 2 5]-related premature mortality during 1990-2010 across the northern hemisphere. Environ Health Perspect 125:400-408; http://dx.doi.org/10.1289/EHP298 [ABSTRACT FROM AUTHOR]