alpha-Defensins are reported to be a soluble component of innate immunity actively participating in host defense against HIV. In order to further investigate the role of alpha-defensins in innate immunity during HIV infection, we analyzed CD8+ T lymphocytes and neutrophils obtained from 34 HIV-infected and 14 uninfected subjects. CD8+ T cells and neutrophils were labelled for evaluating alpha-defensin expression by flow cytometric analysis using a dual laser FACScalibur. Culture supernatants and plasma were also collected for ELISA quantification of alpha-defensins. The results showed a significantly increased production of alpha-defensins in plasma, neutrophils and CD8 T-lymphocytes of patients with HIV infection in comparison with healthy controls. The expression of alpha-defensins, by CD8+ cells probably reflects both the intrinsic production and the uptake from cocultured cells that release defensins. The upregulation of alpha-defensin expression within neutrophils could account for the increased release of such peptides in the systemic circulation. Antiretroviral treatment did not have any effect on plasma levels and expression of alpha-defensins by neutrophils. Overall, our findings suggest that the increased production/expression of alpha-defensins could be correlated with the chronic process of immune activation seen in HIV infection.