The role of HIV-1 resistance-conferring mutations in predicting discordant viro-immunological responses to highly active antiretroviral therapy was investigated. Reverse transcriptase (RT) M184V, and proteases L241 and V82A were significantly associated with an increased CD4 cell count despite virological failure, whereas RT Y181C reduced the probability of immunorecovery. Lower HIV-1-RNA levels in discordant patients and higher values in those carrying RT Y181C suggested a role of viral replicative capacity. Selected mutations should be considered in evaluating the benefit of continuing therapy in discordant patients.