The aim of this study was to evaluate the quality of life and the intensity of the injection site reactions during the first 6 months of treatment with enfuvirtide according to the counseling and training provided by nurses and physicians. In this prospective, 6-month cohort, 61 HIV-1 infected adult patients starting enfuvirtide have been included. At baseline, 82% of the patients have either read information documents (23%) or received counseling (59%); 18% were self-injectors, 27.8% had a dual disposition (self-injector + third person), and 49.2% were injected by a third person. At month 6, among the 43 patients still on enfuvirtide, 59% have had no change in injection disposition, and 52% have the dual disposition. Quality of life and enfuvirtide acceptance improved during 6 months. With adequate education and choice of injection dispositions, treatment with enfuvirtide can lead to quality-of-life improvements.