Contemporary highly active antiretroviral therapy (HAART) is effective and tolerable for a long time but cannot eradicate human immunodeficiency virus (HIV) infection by either elimination of viral reservoirsor enhancement of HIV-specific immune responses. HIV infects the B cell germinal centers in follicles of lymphoid tissue and induces dysfunction, which may persist during HAART, negatively affecting IgG subclass content and the avidity of IgG antibodies. This study investigated the effect of Artemisia annua and Moringa oleifera leaf powder supplementation on p24-specific IgG antibody responses, CD4 count, and viral load among people living with HIV (PLWH) on HAART at an HIV clinic in Uganda. Immunomodulatory effects of A. annua and M. oleifera leaf powder supplementation on viral load, CD4 count, and p24-specific IgG and IgM antibodies among 37 PLWH on antiretroviral therapy were determined by indirect ELISA while chaotrope-based assays were used to determine IgG avidity against the p24 protein. Viral load was determined using the RNA PCR technique. The findings show a statistically significant decrease in the p24-specific IgG antibodies (p = 0.029) while the chaotropicbased assays indicated that HAART supplementation with M. oleifera and A. annua leaf powder was associated with higher IgG antibody avidity against p24 protein (p = 0.026) than the control group. These findings were supported by a statistically significant increase in CD4 count (p<0.001) and viral load suppression (p = 0.035) in the intervention group compared to the control. No statistically significant difference was found in p24-specific IgM antibody titers between the intervention and control groups. Supplementation with a combination of M. oleifera and A. annua leaf powder in patients on highly active HAART diminishes virus-specific B cell responses, suppresses viral replication, and increases CD4 count.