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Background: The impact of different therapeutic classes of drugs in antiretroviral therapy (ART) regimens on the CD4/CD8 ratio is not well documented in people treated for HIV. The objective of this study was to analyze the long-term effect of exposure to integrase strand transfer inhibitor (INSTI) on CD4/CD8 ratio compared with nonnucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) among ART-treated persons with HIV (PWH)., Methods: Data from the Quebec HIV Cohort collected from 31 August 2017 were used. Our analysis included all patients in the cohort who received a first or subsequent ART regimen composed of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and a third active drug of a different class (NNRTI, PI, or INSTI) for at least 16 weeks. Marginal structural Cox models were constructed to estimate the effect of different therapeutic classes on the CD4/CD8 ratio outcome., Results: Among the 3907 eligible patients, 972 (24.9%), 1996 (51.1%), and 939 (24.0%) were exposed to an ART regimen whose third active agent was an NNRTI, PI, or INSTI, respectively. The total follow-up time was 13 640.24 person-years. The weighted hazard ratio for the association between the third active class and CD4/CD8 ratio ≥1 was .56 (95% confidence interval [CI]: .48-.65) for patients exposed to NNRTI + 2 NRTIs and .41 (95% CI: .35-.47) for those exposed to PI + 2 NRTIs, compared with those exposed INSTI + 2 NRTIs., Conclusions: For people treated for HIV, INSTI-based ART appears to be associated with a higher CD4/CD8 ratio than NNRTI and PI-based ART., Competing Interests: Potential conflicts of interest. H. T. has received unrestricted grants from ViiV Healthcare, Merck, and Gilead Sciences and occasional lecture fees from Merck. J.-G. B. has received honoraria for consulting for ViiV Healthcare, Merck, and Gilead Sciences and for participation as a speaker at conferences from Merck and Gilead Sciences unrelated to this work. His institution (Clinique de Médecine Urbaine du Quartier Latin [CMUQL]) has received research grants from GlaxoSmithKline, Merck, and Gilead Sciences. A. d. P.'s institution participates in several pharmaceutical clinical trials for HIV antiretrovirals and hepatitis C virus treatments in which she is the site principal investigator (ViiV Healthcare, Janssen, Merck, Gilead Sciences), and has received honoraria for consulting in advisory board meetings for ViiV Healthcare and Merck. R. T. has received honoraria for consulting for ViiV Healthcare, Merck, and Gilead Sciences, and for participation as a speaker at conferences from Merck and Gilead Sciences. His institution (Clinique Médicale l’Actuel [CMA]) has received research grants from GlaxoSmithKline, Gilead Sciences, Merck, and Janssen. S. C. reports grants or contracts from Canadian Institutes of Health Research (CIHR) Canada Graduate Scholarship—Master's (CGSM). C. T. reports grants or contracts from Merck, CIHR, Gilead, and the National Institutes of Health (NIH); consulting fees from Merck, GlaxoSmithKline, Medicago, Gilead, AstraZeneca, and Moderna; and payment or honoraria for manuscript writing or education event lectures for Merck, GlaxoSmithKline, AstraZeneca, Gilead, Pfizer, and Sanofi. Additionally, C. T. reports support for meetings and/or travel from Moderna and participation on a Data Safety Monitoring or Advisory Board for Colcorona, Dalcor, and Hesperidin. M. K. reports consulting fees from ViiV Healthcare, AbbVie, and Merck, as well as grants or contracts from ViiV Healthcare, AbbVie, Merck, and Gilead for an investigator-initiated study. M. D. reports operating grants from CIHR through the Public Health Agency of Canada and serves as the co-lead for the clinical management core of CIHR HIV Clinical Trial Network. 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) 2023. 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.)