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.