Background: There is no data on long-term benefit of once-a-day antiretroviral therapy (ART) with combination of DDI, 3TC and EFV to allow its use in future therapeutic strategies. Objectives: To assess 24-month immuno-virological, adherence, tolerance, and effectiveness of a once-a-day ART with DDI, 3TC and EFV. Methods: A phase 2 open trial including 51 children aged from 30 months to 15 years, monitored a once-a-day regimen for 24 months from 2006 to 2008 in the Departement de Pediatrie du CHUSS, at Bobo-Dioulasso in Burkina Faso. We tested immunological and virological response, adherence, tolerance and resistance of the treatment. Results: Children with CD4 >25% at 24 months were 67.4% (33/49) CI 95% [54%, 80%].The proportion of children with viral plasma RNA <300 cp / ml at 24 months of treatment was 81.6 % (40/49) CI [68.0% 91.2%]. Good adherence was obtained with more than 88% adherence > 95% over the 24 months. Drugs were well tolerated. Conclusions: Given the limited number of antiretroviral drugs available in Africa and the inadequacy of laboratory monitoring in support program, once-a-day treatment and especially the DDI-based combination strategies could be an attractive operational option.