The aim of this study was to assess whether the density of CD38 antigen expression on CD8+ T cells can be used as a marker of activation of the immune system in Human immunodeficiency virus 1 (HIV-1)-positive patients treated with highly active antiretroviral therapy (HAART). T cell subsets, expression of CD38 antigen on CD8+ T cells, HIV-1 viral load and stage of the disease were analyzed at baseline and after 12 months of HAART in 24 HIV-1-infected patients. Our data showed that the use of HAART is effective in reducing plasma viral load and in achieving a stable CD4+ count and percentage of CD8+/CD38+ cells. The percentages of CD8/CD38+ cells in HIV-1-infected patients at baseline and after 12 months of HAART were significantly higher than those of controls. Analysis of the density of CD38 expression revealed that it was due to CD8+/CD38+ subsets with low and medium density of antigen expression. Absolute number of CD4+ T cells correlated negatively with the percentage of CD8+/CD38+ cells at baseline of the study. Persistent up-regulation of the CD38 expression on CD8+ T cells and its correlation with the decreased CD4+ count despite the reduction of plasma viral load may reflect residual replication of HIV-1 in reservoirs. Thus, this immunological parameter can serve as a biological marker of HIV-1 infection and might have utility in clinical management of HIV-1-infected persons.