OBJECTIVE: Model trajectories of CD4 and CD8 cell counts after starting combination antiretroviral therapy (ART), and use the model to predict trends in these counts and the CD4:CD8 ratio. DESIGN: Cohort study of antiretroviral-naïve HIV-positive adults who started ART after 1997 (ART Cohort Collaboration) with >6 months of follow-up data. METHODS: We jointly estimated CD4 and CD8 count trends and their correlation using a bivariate random effects model, with linear splines describing their population trends, and predicted the CD4:CD8 ratio trend from this model. We assessed whether CD4 and CD8 count trends and the CD4:CD8 ratio trend varied according to CD4 count at start of ART (baseline), and, whether these trends differed in patients with and without virological failure more than 6 months after starting ART. RESULTS: A total of 39,979 patients were included (median follow-up was 53 months). Among patients with baseline CD4 count ≥50 cells/mm, predicted mean CD8 counts continued to decrease between 3 and 15 years post-ART, partly driving increases in the predicted mean CD4:CD8 ratio. During 15 years of follow-up, normalisation of the predicted mean CD4:CD8 ratio (to >1) was only observed among patients with baseline CD4 count ≥200 cells/mm. A higher baseline CD4 count predicted a shorter time to normalisation. CONCLUSIONS: Declines in CD8 count and increases in CD4:CD8 ratio occurred up to 15 years after starting ART. The likelihood of normalisation of the CD4:CD8 ratio is strongly related to baseline CD4 count.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0.