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Loneliness is a growing public health concern worldwide. We characterized the association between cumulative loneliness and subsequent all-cause mortality, using data from 9,032 participants aged 50+ in the population-based US Health and Retirement Study (HRS) from 1996 to 2019. Loneliness status (yes; no) was measured biennially from 1996 to 2004, and we categorized the experience of cumulative loneliness over the 8-y period as never, one time point, two time points, and ≥three time points. A multivariable-adjusted age-stratified Cox proportional hazards regression model was fitted to examine the association between cumulative loneliness from 1996 to 2004 and all-cause mortality from 2004 to 2019. Excess deaths due to each category of cumulative loneliness were calculated. Compared to those who never reported loneliness from 1996 to 2004, participants experiencing loneliness at one time point, two time points, and ≥three time points respectively had 1.05 (95% CI: 0.96 to 1.15), 1.06 (95% CI: 0.95 to 1.19), and 1.16 (95% CI: 1.02 to 1.33) times higher hazards of mortality from 2004 to 2019 (P trend = 0.01). These results correspond to 106 (95% CI: 68 to 144), 202 (95% CI: 146 to 259), and 288 (95% CI: 233 to 343) excess deaths per 10,000 person-years, for those experiencing loneliness at each of one, two, or ≥three time points from 1996 to 2004. Cumulative loneliness in mid-to-later life may thus be a mortality risk factor with a notable impact on excess mortality. Loneliness may be an important target for interventions to improve life expectancy in the United States. [ABSTRACT FROM AUTHOR]