The aim of this study was to evaluate outcome after a genotype guided change of therapy in 18 patients failing HAART. Patients were divided into two groups according to the response to therapy: immune responders (12 patients with immune recovery defined as having more than 100 CD4 cells compared to baseline value), and 6 failing patients (without immune recovery). At month 12 after genotype change of therapy a significant difference in the decrease of HIV-RNA viral load between the two groups of patients was detected (mean -1.95 and +0.04 log HIV-RNA copies/ml, p=0.04). One year after the change of therapy, all but one patients experienced a decrease in the replication capacity of HIV strains. Particularly, the HIV replication capacity of HIV strains decreased from 52% (range 14-98%) to 15.2% (range 0.1-74.5%). The HIV strains of patients failing HAART showed a progressive impaired replication capacity. In patients failing HAART the impaired replication capacity of HIV strains could justify the persistence of an immune recovery.