Rilpivirine is a non-nucleoside reverse transcriptase inhibitor recently developed as a drug of choice for initial treatment of HIV infection. It may however, be associated with the aggravation of metabolic syndrome. Quercetin, a natural flavanoid, is well known for its anti-adipogenic and lipolytic properties. In an attempt to develop treatment and prevention strategies to overcome the metabolic alterations in HIV-infected patients, human subcutaneous pre-adipose cells were used as a model to study the effect of rilpivirine (15 µM) or quercetin (50 µM) either alone or in combination. Immunostaining and qPCR techniques were used to study key adipogenic markers involved in the process of adipogenesis. Data were analyzed statistically using SPSS Version 25 software. Results were analyzed using one-way ANOVA and values of p< 0.05 were considered significant. Quantitative measurement of protein markers show a marked reduction in the levels of PPARγ, CEBPα and its related genes for adipose cells treated with 15 µM of rilpivirine and 50 µM of quercetin individually. Concomitant treatment of adipose cells with these two drugs further reduced these levels. The results from qPCR show that the expression of peroxisome proliferator-activated receptor gamma (PPARγ), CCATT/enhancer-binding protein alpha (C/EBPα) and their related genes. In parallel, the expression of SREBP-1 and its target genes like FAS, aP2 and LPL were all significantly decreased displaying the lipoatrophic and anti-adipogenic effects of rilpivirine and quercetin respectively. The results indicate that rilpivirine alters adipogenesis through the down-regulation of adipogenic transcriptional factors and their target genes. The study also, for the first time, reports that co-administration of rilpivirine and quercetin further down regulated the expression of these markers and quercetin failed to overcome the lipoatrophic affects of rilpivirine. In conclusion, the results have demonstrated that both rilpivirine and quercetin can down regulate PPARγ, C/EBPα and SREBP-1 together with their target genes, FAS, aP2 and LPL. However, further studies are required to investigate the mechanism(s) of interaction of the two drugs and more clinical research studies are needed to develop quercetin as a proven natural and effective agent for the antiretroviral therapy-induced prevention or treatment of metabolic disturbances.