ZAP-70 is a critical protein tyrosine kinase in T-cell activation and proliferation processes. Defective recruitment of ZAP-70 molecules results in termination of the T-cell receptor (TCR) signal transduction pathway. Impairment of this pathway is one of the early markers of disease progression in HIV-1 infected individuals. T-cell dysfunction in HIV infected patients may be connected to a defect in the proximal TCR signaling cascade. To evaluate this presumption, the numbers and mean fluorescence intensity (MFI) of ZAP-70 positive cells in patients with treated and untreated HIV-1 infection and healthy controls were analyzed by flow cytometry. A correlation between the MFI in ZAP 70 molecules and the viral load was evaluated. A total of 41 HIV-1 infected patients, 30 patients on HAART and 11 untreated patients, and 11 healthy controls were enrolled. The data show ZAP-70+/CD4+ cells in treated and untreated HIV-1 infected individuals had a greater MFI of ZAP-70 molecules than those from healthy controls (p < 0.001). The inverse correlation between the percentage of CD4+cells and the MFI of ZAP-70+/CD4+ T-cells was significant (r = -0.5; p < 0.01). A stronger correlation between the percentage of CD4+/CD25+ cells and the MFI of ZAP-70+/CD4+ cells was observed (r =-0.6; p < 0.01). However, no significant correlation was seen between the MFI of the ZAP-70+/CD4+cells and the viral load in patients with untreated HIV-1 infection (r = -0.4, p = 0.16). For HIV-1 treated patients, the viral loads were too low to detect so it was not possible to calculate the correlation. Elevated MFI levels of ZAP-70 molecules in CD4+ cells in HIV infected patients may be associated with an inability to further activate T-cells.