Introduction: Rapid scale-up of antiretroviral therapy (ART) in the context of financial and health system constraints has resulted in calls to maximize efficiency in ART service delivery. Adopting differentiated care models (DCMs) for ART could potentially be more cost-efficient and improve outcomes. However, no study comprehensively projects the cost savings across countries. We model the potential reduction in facility-level costs and number of health workers needed when implementing two types of DCMs while attempting to reach 90-90-90 targets in 38 sub-Saharan African countries from 2016 to 2020.Methods: We estimated the costs of three service delivery models: (1) undifferentiated care, (2) differentiated care by patient age and stability, and (3) differentiated care by patient age, stability, key vs. general population status, and urban vs. rural location. Frequency of facility visits, type and frequency of laboratory testing, and coverage of community ART support vary by patient subgroup. For each model, we estimated the total costs of antiretroviral drugs, laboratory commodities, and facility-level personnel and overhead. Certain groups under four-criteria differentiation require more intensive inputs. Community-based ART costs were included in the DCMs. We take into account underlying uncertainty in the projected numbers on ART and unit costs.Results: Total five-year facility-based ART costs for undifferentiated care are estimated to be US$23.33 billion (95% confidence interval [CI]: $23.3–$23.5 billion). An estimated 17.5% (95% CI: 17.4%–17.7%) and 16.8% (95% CI: 16.7%–17.0%) could be saved from 2016 to 2020 from implementing the age and stability DCM and four-criteria DCM, respectively, with annual cost savings increasing over time. DCMs decrease the full-time equivalent (FTE) health workforce requirements for ART. An estimated 46.4% (95% CI: 46.1%–46.7%) fewer FTE health workers are needed in 2020 for the age and stability DCM compared with undifferentiated care.Conclusions: Adopting DCMs can result in significant efficiency gains in terms of reduced costs and health workforce needs, even with the costs of scaling up community-based ART support under DCMs. Efficiency gains remained flat with increased differentiation. More evidence is needed on how to translate analyzed efficiency gains into implemented cost reductions at the facility level.