The objectives of this study were to determine the prevalence of osteopenia and the factors associated with its presence in HIV-infected patients under highly active antiretroviral therapy (HAART) and to assess the changes of bone mineral density (BMD) in a population followed prospectively. BMD was assessed by dual-energy X-ray absorptiometry (DEXA) scans at the lumbar spine and at the femoral neck in 78 HIV-infected patients who had previously received HAART as the first antiretroviral regimen and in 11 antiretroviral-naive HIV-infected patients. BMD measurements were repeated in 70 treated patients who had completed 1 year of follow-up. Thirty-seven (42%) patients showed osteopenia at any localization. The prevalence of osteopenia in PI-naive patients was 23% versus 49% in individuals who had received PI at any moment [p = .001; adjusted odds ratio (95% CI) = 0.11 (0.02-0.48)]. The frequency of osteopenia was significantly higher among men than among women [50% vs. 17%; p = .016; adjusted OR (95% CI) = 12.1 (2.22-66.20)]. The level of plasma albumin was independently associated with osteopenia [adjusted OR (95% CI) per each g/dL of plasma albumin decrease 2.55 (1.18-10)]. In patients in whom a second DEXA was done, no significant changes in BMD were found. The prevalence of osteopenia in HIV-infected patients on HAART is high. Loss of BMD is associated with PI therapy, low plasma albumin level, and male sex. Osteopenia does not progress after 1 year of continued HAART.