Background: HIV-infected patients display an increased and early incidence of osteopenia/osteoporosis. We investigated whether bone metabolism disorders in HIV-infected patients are related to immune hyperactivation and premature immune senescence. Methods: Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA): low BMD (LBMD) was defined as T-score or z-score < -1. CD4+/CD8+ phenotype (CD38/HLA-DR, CD127, CD28/CD57), and circulating IL-7, TNF-α, RANKL, OPG were measured. The variables with p < .05 were evaluated by multivariate logistic regression. Results: 78 patients were enrolled: 55 were LBMD. LBMD patients showed increased activated HDLADR + CD4+ and CD8+ (p = .03 and p = .002, respectively). Interestingly, no differences in senescent CD28-CD57 + CD4+/CD8+ T-cells were observed between groups. However, LBMD patients displayed a decreased CD4 + CD28- phenotype (p = .04) at the advantage of the CD28+ pool (p = .03), possibly reflecting heightened apoptosis of highly differentiated CD28-negative cells. Activated HLADR + CD4+/CD8+ and CD28 + CD4+ cells were independently associated with impaired BMD (AOR = 1.08 for each additional HLADR + CD4+ percentage higher; CI 95%,1.01-1.15; p = .02; AOR = 1.07 for each additional HLADR + CD8+ percentage higher; CI 95%,1.01-1.11; p = .01; AOR = 1.06 for each additional CD28 + CD4+ percentage higher; CI 95%,1.0-1.13; p = .05). Conclusions: Heightened T-cell activation in HIV-infected patients independently predicts BMD disorders, suggesting a critical role of immune activation in the pathogenesis of osteopenia/osteoporosis, even in patients achieving full viral suppression with HAART.