Objective: To study virologic and immunologic factors associated with discordant treatment response in HIV-infected patients receiving highly active antiretroviral therapy (HAART). Design: Study participants included a total of 27 patients: (a) 10 discordant patients (mean CD4+ cell count, 396.1 × 106 cells/l; mean HIV-RNA, 5.4 log10 copies/ml); (b) seven responder patients (mean CD4+ cell count, 997.5 × 106 cells/l); and (c) 10 failing patients (mean CD4+ cell count 66.5 × 106 cells/l; mean HIV-RNA, 5.4 log10 copies/ml). Methods: The HIV-1 isolation rate and biological phenotype, drug resistance genotypic mutations of HIV-1 strains, recall and HIV-1-specific antigen lymphocyte proliferation (LP), and interleukin (IL)-15 production were studied. Results: Virus isolation was obtained in 30% of discordant patients, and in 100% of failing patients. A higher replication constant was reported in discordant patients. No difference in the number of drug resistance mutations and biological phenotypes of HIV-1 was found in discordant patients with respect to failing patients. Discordant patients developed positive LP responses to Candida albicans and HIV-1 p24. LP in response to C. albicans, HIV-1 p24 and gp160 was positive in responder patients. No significant LP was found in failing patients. Increased levels of IL-15 after stimulation with lipopolysaccaride (LPS) and C. albicans were found in both discordant patients and responder patients. Conversely, a strong reduction of IL-15 levels was observed in failing patients. Conclusion: The present results suggest that decreased virus isolation rate, restoration of both lymphocyte proliferation and IL-15 production are factors involved in the discordant antiretroviral therapy response of HIV-infected patients. © 2002 Lippincott Williams & Wilkins.