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Osteopenia is common in the era of effective antiretroviral therapy (ART), yet the etiology is unclear. We evaluated the association of host factors, disease severity, and ART to changes in total body bone mineral density (total BMD) over time in HIV-infected men (n = 283) and women (n = 96).Total BMD was measured annually by whole-body dual-energy absorptiometry (DXA), and medical, dietary, and behavioral history was collected. The median time from first to last DXA was 2.5 years (range 0.9-6.8 years). Using a repeated measures regression model, we identified variables independently associated with percent change in total BMD between consecutive DXA exams (n = 799 intervals), adjusted for age, race, sex, menopause, and smoking. We estimated percent change in total BMD over an average interval (1 year) standardized for representative levels of each determinant in males, premenopausal women, and postmenopausal women.Median baseline age, CD4, and viral load were 42 years, 364 cells per cubic millimeter, and 2.7 log10 copies per milliliter, respectively. The estimated change in total BMD for those not on ART was −0.37% per year [95% confidence interval (CI) −0.76 to −0.02] for men, −0.08% per year (95% CI −0.49 to 0.33) for premenopausal women, and −1.07% per year (95% CI −1.86 to −0.28) for postmenopausal women. Greater loss of total BMD was associated with lower albumin, lower body mass index, prednisone/hydrocortisone use, tenofovir use, and longer duration of didanosine. Strength training and long duration of d4T and saquinavir prevented or mitigated bone loss. For those on ART for 3 years (not including the above agents), the rate of loss was −0.57% per year (95% CI −1.00 to −0.14) for men, −0.28% (95% CI −0.71 to 0.15) for premenopausal women, and −1.27% (95% CI −2.07 to −0.47) for postmenopausal women. Postmenopausal women had greater loss than premenopausal women and men.Low body weight, low albumin, catabolic steroid use, and menopause may accelerate bone loss, and strength training may be protective. Tenofovir and didanosine may also have a deleterious effect on BMD.