: Antiretroviral therapy initiation is associated with declines in bone mineral density (BMD), which seem greatest with tenofovir disoproxil fumarate (DF)-containing regimens. Data comparing protease inhibitors are limited. This CASTLE substudy compared paired baseline with week 96 BMD in patients initiating tenofovir DF/emtricitabine plus atazanavir/ritonavir (n = 106) vs lopinavir/ritonavir (n = 70). In both groups, week 96 BMD declined significantly in arm, leg, trunk, and total body regions. Atazanavir/ritonavir was associated with smaller 96-week trunk and total body BMD declines compared with lopinavir/ritonavir [multivariate-adjusted least squares mean difference +2.00% (95% confidence interval: 0.52 to 3.45; P = 0.008) and +1.24% (95% confidence interval: 0.13 to 2.35; P = 0.029), respectively]. In addition, low baseline CD4 cell count (<50 cells per microliter) and increasing age were associated with larger declines in BMD.