Raltegravir is an HIV-1 integrase inhibitor that is currently licensed for use in treatment-experienced HIV-1 patients and recently approved for use in treatment-naïve patients. Recent data has shown that the virologic response in patients on raltegravir with no history of antiretroviral treatment (ART) was equal to efavirenz-based therapy at 96-weeks (combined with tenofovir/lamivudine). Moreover, raltegravir demonstrated greater immunologic effect, had fewer adverse side effects and had a neutral effect on lipid levels. Further support for first-line use comes from recent 48-week data of a subgroup analyses of the STARTMRK Phase III study comparing raltegravir to efavirenz-based therapy (with tenofovir/emtricitabine) in treatment-naïve patients that showed non-inferior virologic and immunologic efficacy with raltegravir. There were significantly fewer overall and drug-related clinical adverse events in the raltegravir group and a similar safety profile in patients with hepatitis B and/or C co-infection. These findings suggest that use of raltegravir as a component of initial therapy might be beneficial in patients with significant co-morbidities such as hepatitis C and in situations where there is concern of interactions between antiretrovirals and other drugs.