Background: The severe shortage of pharmacists is an important limitation to providing antiretroviral treatment (ART) in resource-limited countries. Two task-shifting pharmaceutical care models have been developed to address this in South Africa, namely indirectly supervised pharmacist assistant (ISPA) and nurse-managed models. This study compared pharmaceutical care quality, patient clinical outcomes, and provider staff costs between these models. Methods: An analysis of pharmaceutical quality audits, patient clinical data, and staff costing data collected at 7 ISPA and 8 nurse-managed facilities was undertaken. Pharmaceutical audits were conducted by pharmacists using a standardized tool. Routine clinical data were collected prospectively at patient visits, and staff human resources costs were analyzed. Results: Overall pharmaceutical care quality scores were higher at ISPA sites than nurse-managed sites; 88.8% vs. 79.9%, respectively; risk ratio (ISPA vs. nurse) = 1.11 (95% confidence interval: 1.09 to 1.13; P < 0.0001). Mean provider pharmaceutical-related human resources costs per patient visit and per item dispensed were 29% and 49% lower, respectively, at ISPA facilities. At ISPA facilities, patient attrition was observed to be lower and viral suppression higher than at nurse-managed sites. Conclusion: The ISPA model had a higher quality of pharmaceutical care and was less costly to implement. Further expansion of this model or integrating it with nurse-managed ART may enhance the cost-efficient scale-up of ART programs in Sub-Saharan Africa.