Enfuvirtide is a fusion inhibitor used for the treatment of HIV infection. It is an injectable drug, with the patient being responsible for reconstitution as well as injection. The authors present the results of Phase III trials with enfuvirtide. A summary of efficacy, tolerability, pharmacokinetics, resistance, and adverse events from the Phase III trials with enfuvirtide is presented. Enfuvirtide is well tolerated, and no limiting pharmacokinetic interactions have been published thus far. A review of patient perception of self-injection is also summarized. The data reviewed demonstrate that most patients find self-injection easy and do not find that it interferes with activities of daily living. Data on injection site reactions (ISRs), one of the most common adverse events of enfuvirtide, is highlighted, as is nursing management of ISRs. Finally, the authors discuss research that could help further understanding of enfuvirtide and examine some barriers clinicians may face when prescribing this medication.