Determination of HIV-1 subtype may be important in the management of HIV-infected individuals, particularly with regard to deciding the CD4 cell count at which to initiate antiretroviral therapy. Non-B subtypes, A and D, are prevalent in Uganda, and individuals infected with subtype D seem to have faster disease progression compared with those infected with subtype A. We examined the level of apoptosis in CD4+ T cells in a study cohort of volunteers infected with subtypes A and D infection. Although the levels of apoptosis in the activated CD4+ cells significantly decreased with viral suppression, CD4+ apoptosis in individuals infected with subtype D were found to be significantly higher compared with those infected with subtype A before antiretroviral treatment. Surface expression of PD-1 on CD4 cells in subtype D was substantially higher compared with that in subtype A (P = 0.03). This difference was not observed in the CD8 population (P > 0.05). Our findings suggest that the infecting HIV subtypes exert an independent influence on the disease outcome in response to antiretroviral treatment.