Highly active anti-retroviral therapy (HAART) has significantly improved the prognosis of HIV-1-infected patients, but it is associated with the aggravation of a metabolic syndrome with potentially severe consequences like dyslipidemia, insulin-resistance and overt lipodystrophy (re-distribution of body fat). The HAART-induced inflammation is normally exerted in the form of altered cytokine release, adipocyte dysfunction, metabolic disturbances and oxidative stress as part of the body’s effort to fight the virus. Rilpivirine is a non-nucleoside reverse transcriptase inhibitor recently developed as a drug of choice for initial anti-retroviral treatment of HIV infection. Quercetin, a natural flavanoid, is well known for its anti-adipogenic and lipolytic properties. This study investigated the anti-adipogenic properties of quercetin to overcome the adverse metabolic side effects incurred due to the anti-retroviral therapy, using rilpivirine. In vitro studies using human subcutaneous pre-adipose cells were used to model the adverse effects of rilpivirine and the beneficial physiological role of quercetin either alone or in combination to combat the adverse effects of rilpivirine. The results show that either rilpivirine (10 µM and 20 µM) or quercetin (50 µM) either alone or when combined had little or no significant effect on adipose cell viability over 15 days, as measured by lactate dehydrogenase (LDH) release compared to untreated cells. However, there were significant (p<0.05; ANOVA) reductions in the accumulation of triglyceride levels and evidenced by morphological changes of the cells on the 5th, 8th, 11th and 15th day of the differentiation process with both drugs. Rilpivirine at 20 µM alone or in combination with quercetin severely inhibited triglyceride accumulation during adipocyte differentiation. In the second set of experiments, pre-adipocytes were treated with either rilpivirine or quercetin alone and in combination for the quantitative measurement of adipocytokines as well as oxidative stress markers. The results also show that rilpivirine (15 µM) can significantly (p<0.05) reduced the release of adiponectin and increased the release of resistin and IL-8, but with no effect on leptin level. On the other hand quercetin (20 µM) can reverse these effects of rilpivirine even alone or when combined compared to untreated cells. The data also reveal that rilpivirine can induce significant (p<0.05) decreases in the activities of the anti-oxidant enzymes, superoxide dismutase, catalase and glutathione from adipose cells, accompanied by a significant increase in the nitric oxide levels. Again, quercetin treatment reversed these effects of rilpivirine either alone or in combination. The results have clearly demonstrated the beneficial physiological role of quercetin to combat the adverse effects of rilpivirine during the process of adipogenesis.