OBJECTIVES: Drugs used in the treatment of Human Immunodeficiency Virus (HIV) which form part of Highly Active Anti-retroviral Therapy (HAART) are usually expensive and may have serious side effects.  The objective of this study was to compare the costs and adverse events of a new therapeutic agent, Rilpivirine, with an established agent, Efavirenz, used in the treatment of HIV, both of which form part of HAART among treatment naïve patients.  METHODS: Decision tree analysis was used to compare the direct medical costs of using Rilpivirine versus Efavirenz in HAART from the societal perspective.  Drug costs were obtained from an online drug information source and Red Book 2008.  Base case probabilities of having an adverse event were obtained from a published clinical trial comparing Rilpivirine versus Efavirenz (N=690).  Costs for treating adverse events were obtained from the Medical Expenditure Panel Survey Database (2008). All costs were converted into 2011 US dollars.  Sensitivity analyses were performed to determine the effects of variations in assumptions regarding drug costs and costs for treating adverse events on study results.  All analyses were conducted using the 2011 Tree Age Pro Software.      RESULTS: The analyses showed that Rilpivirine is the treatment of choice in the first year of therapy with a net cost of $27,282 per patient for Rilpivirine as compared to $28,619 per patient for Efavirenz.  These results were robust to changes in assumptions about costs of adverse events.  If the cost of Rilpivirine was higher than $11,610 or if the cost of Efavirenz was lower than $6,387, Efavirenz would be the treatment of choice.         CONCLUSIONS: From a societal standpoint, Rilpivirine as part of HAART costs less as compared to Efavirenz.  Future studies should aim at comparing Rilpivirine with other established drugs used in the treatment of HIV.