The latest WHO guidelines (2010) for antiretroviral therapy (ART) in adults and adolescents recommend that countries should progressively reduce the use of stavudine in favour of tenofovir or zidovudine and that ART initiation commence at an earlier CD4 threshold of <350 cell/mm(3). In Lesotho, a high-burden, resource-limited setting, these two changes had been recommended since late 2007. A number of practical steps were taken to support implementation of Lesotho's national ART guidelines at the program level including: development of guidelines tailored to nurses working in primary care settings; training and clinical mentorship of different levels of health care workers; laboratory support; pharmacy support; and monitoring and evaluation. Clinical and programmatic benefits included decreased mortality, toxicity, and simplified patient management that was supportive of the decentralized, nurse-led model of care. This experience demonstrates that, despite limited resources, it was feasible to provide a standard of care similar to that of western guidelines and that these changes were supportive of simplified patient management.