The time has come that Sub-Saharan Africa benefit from implementation of Evidence-Based Interventions (EBIs) that have been developed over time in the United States, Europe, and by the United Nations (UN) agencies. This paper has been written partly because less information is coming out of Africa regarding diffusion and implementation of EBIs. There is a need to highlight and reflect on the delivery of interventions of human immunodeficiency virus (HIV) and substance use(r) programs in Sub-Saharan Africa. Both the evidence and practices may help enrich discussions as a way to improve the quality of program outcome in the region and at the same time retire inappropriate old interventions "Prevention can work, but not everything called prevention works" Belinda E. Sims (2011).