Different approaches applied to prepare in situ forming implants for controlled delivery of enfuvirtide, an anti HIV fusion inhibitor. An injectable, phase sensitive, in situ forming, implantable delivery system was developed for enfuvirtide, a therapeutic peptide used in the treatment of HIV infection. The development studies were carried out using poly (d,l-lactide-co-glycolide), a smart, biodegradable polymer. Different formulations were designed, prepared and evaluated by employing response surface, optimal design of experiment technique. The optimized formulation was identified and validated for its performance by using numerical optimization technique. The in vitro evaluation parameters included rheology, compatibility studies, drug release as well as conformational and physicochemical stability studies. In vivo pharmacokinetic parameters and biocompatibility studies were determined in rat models and were statistically analyzed. It was found that the optimized formulation extended the enfuvirtide release and maintained the drug plasma concentration within therapeutically effective range up to 48h. The optimized formulation maintained physicochemical and conformational stability for at least 6 months and was biocompatible with the animal tissue.