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Background: Mortality among people with human immunodeficiency virus (HIV) declined with the introduction of combination antiretroviral therapy. We investigated trends in mortality in people with HIV from 1999 through 2020., Methods: Data were collected from the Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) cohort between January 1999 through January 2015 and the International Cohort Consortium of Infectious Disease (RESPOND) from October 2017 through December 2020. Age-standardized all-cause and cause-specific mortality rates, classified using Coding Causes of Death in HIV, were calculated. Poisson models were used to assess mortality over time., Results: Among 55 716 participants followed for median 6 years (interquartile range, 3-11), 5263 died (mortality rate [MR], 13.7/1000 person-years of follow-up [PYFU]; 95% confidence interval [CI], 13.4-14.1). Changing mortality was observed: AIDS mortality was most common between 1999-2009 (n = 952; MR, 4.2/1000 PYFU; 95% CI, 4.0-4.5) and non-AIDS-defining malignancy (NADM) between 2010-2020 (n = 444; MR, 2.8/1000 PYFU; 95% CI, 2.5-3.1). In multivariable analysis, all-cause mortality declined (adjusted mortality rate ratio [aMRR], 0.97 per year; 95% CI, .96-.98), mostly 1999-2010 (aMRR, 0.96 per year; 95% CI, .95-.97) but was stable 2011-2020 (aMRR, 1.00 per year; 95% CI, .96-1.05). Mortality due to all known causes except NADM also declined., Conclusions: Mortality among people with HIV in the D:A:D and/or RESPOND cohorts declined between 1999-2009 and was stable over the period 2010-2020. This decline in mortality was not fully explained by improvements in immunologic-virologic status or other risk factors., Competing Interests: Potential conflicts of interest . A. M. reports consulting fees from Eiland and Bonnin. H. F. G. reports honoraria for data and safety monitoring board or advisory board membership from Merck, Gilead Sciences, ViiV Healthcare, GSK, Janssen, Johnson & Johnson, and Novartis; a travel grant from Gilead Sciences; unrestricted research grants from Gilead Sciences; grants or contracts paid to institution from the Swiss National Science Foundation, Swiss HIV Cohort Study, National Institute of Health; and an unrestricted research grant from Gilead Sciences, Yvonne Jacob Foundation. J. J. V. reports personal fees from Merck Sharp & Dohme, Gilead, Pfizer, Astellas Pharma, Basilea, German Centre for Infection Research (DZIF), University Hospital Freiburg/ Congress and Communication, Academy for Infectious Medicine, University Manchester, German Society for Infectious Diseases (DGI), Ärztekammer Nordrhein, University Hospital Aachen, Back Bay Strategies, German Society for Internal Medicine (DGIM), Shionogi, Molecular Health, Netzwerk Universitätsmedizin, Janssen, NordForsk, Biontech, and APOGEPHA and grants from Merck Sharp & Dohme, Gilead, Pfizer, Astellas Pharma, Basilea, German Centre for Infection Research (DZIF), German Federal Ministry of Education and Research (BMBF), Deutsches Zetrum für Luft- und Raumfahrt (DLR), University of Bristol, Rigshospitalet Copenhagen, and Network University Medicine. F. W. reports personal fees for attending advisory boards from ViiV Healthcare. A. d’A. M. reports fees for lectures sponsored by ViiV, Gilead, and Pfizer and projects sponsored (to institution) by ViiV, Gilead, and Merck Sharpe & Dohme. V. S. reports CME education fees from Gilead Sciences, Merck Sharp & Dohme, and ViiV Healthcare. C. C. reports an unrestricted Nordic Fellowship Grant from Gilead Sciences Nordic; honoraria from GSK and ViiV, Gilead Sciences, and Merck Sharp & Dohme (paid to institution), and has participated on an advisory board for GSK, ViiV and Gilead Sciences (paid to institution). P. S. reports honoraria and/or speaking fees from Gilead, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, and ViiV Healthcare and a research grant from ViiV Healthcare, all outside of the submitted work. A. C. reports consulting fees from Gilead Sciences, Merck Sharp & Dohme, and ViiV Healthcare; honoraria for presentations from Gilead Sciences and ViiV Healthcare; support for travel to advisory board and to study investigator meetings from Merck Sharp & Dohme; and receipt of study medication and supplies from Merck Sharp & Dohme. K. P. reports unrestricted research funding made to institution by Gilead Australia and ViiV Healthcare Australia. F. Bonnet reports grants from Gilead and ViiV Healthcare and honoraria from Gilead, ViiV Healthcare, and Merck Sharp & Dohme. S. D. W. reports payments from the D:A:D and RESPOND studies paid to institution. J. G. is an employee of Gilead Sciences. V. V. is an employee of ViiV Healthcare. L. Y. is an employee of Merck Sharp & Dohme. C. S. reports honoraria for preparation of educational materials from Gilead Sciences and honoraria for speaking and preparation of educational materials from ViiV Healthcare. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)