With the increasing access to antiretroviral therapy in sub-Saharan African HIV-positive populations, it is important to find additional simple, effective, and feasible methods of improving and maintaining adequately high levels of adherence. In this study, we undertook the development, testing, implementation, and evaluation of various adherence support interventions at four sites in Uganda. A one-group pre- and post-intervention design was employed under routine operational conditions. Various adherence support strategies were identified, adapted, and developed. These strategies which included a combination of elements such as counseling, group education, leaflets, late attendee tracing, and adherence diaries was implemented for an antiretroviral treatment cohort which had baseline levels of adherence measured preintervention. Follow-up was from August 2009 through August 2010. Mean adherence and proportions of clients achieving adherence levels of 95% and above were determined at end of follow-up. Of the 967 participants enrolled, 856 (88.5%) completed follow-up. A before-and-after comparison of outcomes demonstrated that mean adherence (95% confidence interval [CI]) improved statistically significant from baseline following implementation of the interventions (97.4% [96.9-97.9%] to 99.1% [99.0-99.3%], P=0.001). There was also a significant difference between proportions with optimal (≥ 95%) and suboptimal adherence (<95%) pre- and post-intervention (7.0% difference, 95% CI: 4.6-9.4%, P<0.001). We conclude that additional adherence strategies (including counseling, group education, leaflets, late attendee tracing, and adherence diaries) can substantially improve and maintain high levels of treatment adherence in the long term. Health systems in sub-Saharan African countries should consider integrating these elements into their treatment programs for HIV/AIDS.