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 more than 6 months of follow-up data. METHODS: We jointly estimated CD4 and CD8 cell 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 cell count trends and the CD4 : CD8 ratio trend varied according to CD4 cell 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 cell count at least 50 cells/μl, predicted mean CD8 cell 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, normalization of the predicted mean CD4 : CD8 ratio (to >1) was only observed among patients with baseline CD4 cell count at least 200 cells/μl. A higher baseline CD4 cell count predicted a shorter time to normalization. CONCLUSION: Declines in CD8 cell count and increases in CD4 : CD8 ratio occurred up to 15 years after starting ART. The likelihood of normalization of the CD4 : CD8 ratio is strongly related to baseline CD4 cell count.