OBJECTIVE: To analyse the efficiency of adding Enfuvirtide (ENF) to an Optimised Therapy (OT) in HIV patients who are resistant to the atirretroviral (ARV) drugs available. METHODS: A Markov model was developed to simulate the clinical progression of the population analyzed in the clinical trial with a 48 weeks treatment period. A cost-effectiveness analysis of ENF in terms of incremental cost per life year gained (LYG) was obtained. The model was designed over a time horizon of 10 years with monthly cycles and taking into account the perspective of the Spanish National Health Service. The primary clinical outcome was time until death. Efficacy rates and transition probabilities were obtained from reported clinical and epidemiological trials. Resource use data was retrieved from published literature in the Spanish setting and a panel of clinical opinion leaders. Unit costs were converted to euros and adjusted for the year 2003. RESULTS: Adding ENF to OT increases patient's life expectancy by 1.6 years. Total costs are €117,375 for OT and €159,121 with ENF + OT, mainly due to the fact that increasing life expectancy for a given cohort of patients, increases resource use and costs. Incremental cost per life year gained with ENF is €25,687, which is similar to the value previously reported when considering results with only 24 weeks of treatment (€24,780). CONCLUSIONS: ENF used in combination with an OT regimen increases life expectancy for HIV-1 treated patients who are highly ARV-experienced and delays onset of new AIDS-defining events, resulting in an economically efficient treatment option.