Background: Tenofovir alafenamide (TAF) has replaced tenofovir disoproxil fumarate (TDF) in many clinical settings. However, concerns remain about potential metabolic complications of TAF. We aimed to evaluate changes in weight, laboratory markers, and metabolic-related clinical events after replacing TDF with TAF., Methods: Multicenter prospective cohort study in the Spanish CoRIS cohort. We included virologically suppressed adults with human immunodeficiency virus (HIV) receiving TDF for more than 12 months who either switched to TAF or maintained TDF, with no changes in the core agent. Participants were matched by propensity score. We fitted generalized equation models to assess changes in weight, blood lipids, and hepatic steatosis index, and to compare the incidence of diabetes, hypertension, and lipid-lowering drug use after 144 weeks., Results: In total, 1446 participants were matched in each group. Median age was 38 years, 85% were male, mean weight at baseline was 73 kg. Participants who switched to TAF had a mean weight increase of +0.5 kg at 144 weeks over those who maintained TDF, with no difference in the occurrence of overweight or obesity. Individuals who switched to TAF had a significant increase in total cholesterol (+7.9 mg/dL) and triglycerides (+11.2 mg/dL), with no differences in the total cholesterol-high-density lipoprotein (HDL) ratio. However, no increased incidence of diabetes, hypertension, or lipid-lowering drug use was observed after the follow-up period., Conclusions: Switching from TDF to TAF is associated with modest weight gain and increases in total cholesterol and triglycerides, without an impact on the incidence of obesity or metabolic-related clinical events, in this Spanish cohort with a majority White male population., Competing Interests: Potential conflicts of interest. J. M.-S. reports personal fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from ViiV Healthcare, Janssen Cilag, Gilead Sciences, and Merck Sharp & Dohme (MSD) and non-financial support from ViiV Healthcare, Jannsen Cilag, and Gilead Sciences, including support for attending meetings and/or travel, outside the submitted work. A. M. d. C. reports personal fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from ViiV Healthcare, Janssen Cilag, Gilead Sciences, and MSD and non-financial support from Jannsen Cilag and Gilead Sciences, including support for attending meetings and/or travel. S. M. reports grants, personal fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, participation on a Data Safety Monitoring Board or Advisory Board, support for attending meetings and/or travel, and non-financial support from ViiV Healthcare; personal fees, grants or contracts, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, participation on a Data Safety Monitoring Board or Advisory Board, support for attending meetings and/or travel and non-financial support from Janssen; grants, personal fees, participation on a Data Safety Monitoring Board or Advisory Board and non-financial support including support for attending meetings and/or travel from MSD; grants, personal fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, support for attending meetings and/or travel, participation on a Data Safety Monitoring Board or Advisory Board and non-financial support from Gilead, outside the submitted work, and grants or contracts from the Instituto de Salud Carlos III. S. S.-V. reports grants or contracts from Instituto de Salud Carlos III (ICI20/00058, COV20/00349, PI21/00041) and from Merck (IISP 60257, IISP 59181); personal fees from Gilead Sciences; as well as non-financial support from ViiV Healthcare, Merck and Gilead Sciences; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead Sciences; support for attending meetings and/or travel from ViiV and Gilead; patents planned, issued or pending (EP19382159, “Anal bacterial biomarkers for the diagnosis of anal precancerous lesions” and EP21382486, “Biomarker and methods to predict susceptibility to SARS-CoV-2 and COVID19 severity”), and research grants from MSD, outside the submitted work. All other authors report no potential conflicts. 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) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)