Background Immune activation and exhaustion drive several co-morbidities and disease progression in HIV-infected adults; however, they are not well-studied in HIV-infected youth. Thus, this study sought to examine levels of immune activation and exhaustion in this population, investigate associated HIV- and non-HIV-related variables, and compare results with a matched healthy control group. Methods HIV-infected youth 8–25 years old on stable antiretroviral therapy with an HIV-1 RNA level <1000 copies/mL were enrolled, along with matched healthy controls. We measured T-cell and monocyte immune activation and exhaustion markers in cryopreserved PBMC and plasma samples. Results 136 subjects (80 HIV+: 66% male; 91% black) were enrolled. Markers of CD4+ and CD8+ T-cell activation were higher in the HIV-infected group vs. controls [mean % CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ = 2.2 vs. 1.5 (P=0.002) and 4.9 vs. 2.2 (P<0.0001), respectively], as were exhausted CD4+ and CD8+ T-cells [mean % CD4+CD38+HLA-DR+PD-1+ and CD8+CD38+HLA-DR+PD-1+ = 1.0 vs. 0.5 (P<0.0001) and 1.6 vs. 0.7 (P<0.0001), respectively]. There were no differences in proportions of inflammatory or patrolling monocytes between groups (P>0.05); however, soluble CD14 was higher in HIV-infected compared with controls (1.6 vs. 1.4 μg/mL; P=0.01). Current CD4 count, low-density lipoprotein cholesterol, and age were the variables most associated with CD4+ and CD8+ T-cell activation. Conclusions CD4+ and CD8+ T-cell immune activation and exhaustion are higher in HIV-infected youth compared with matched controls, while monocyte sub-populations are not altered despite a high soluble CD14 level. The clinical significance of the increased immune activation and exhaustion should be further explored.