The monitoring of the efficacy of anti-retroviral therapy (ART) is becoming an important issue in the developing world. The current use of CD4 counts, plasma viral loads, and monitoring of drug-resistant viruses are at present either uninformative or costly. Thus, more new cost-effective and practical techniques need to be established and implemented. Towards this goal, our lab has carried out studies on the potential use of CD38 frequency and density expression by flow analysis as a means to assess the efficacy of ART. Results of our studies using whole blood sample from normal healthy donors indicate that CD38 is expressed by a high frequency of not only CD4+ and CD8+ T cells but also most hematopoietic cell lineages analyzed. Detailed studies of CD38 expression along with other cell surface markers using whole blood sample from HIV-1-infected patients showed that the most discriminating change was the increased frequency and density of CD38 expression by CD3+CD8+ T cells. Of importance was our preliminary finding that a reversal of the increased frequency and density of CD38 expression by CD8+ T cells only appeared in the whole blood sample from patients who were responders to ART but not those who were drug failures. These initial data provide a platform and incentive for larger cohort studies including prospective pre- and post-ART for the institution of such monitoring techniques in resource limited settings.