Cystatin A is a natural cysteine proteinase inhibitor and is found in a wide variety of normal cells. The physiologic role of Cystatin A is not fully known, however. Cystatin A is present in large amounts in follicular dendritic cells, which are important in HIV-1 pathogenesis. We analyzed Cystatin A expression in tonsillar sections from 20 patients at various stages of HIV-1 infection. There was a significant (P < 0.001) difference in Cystatin A fractions between patients and controls, with medians (ranges) of 0.61 (0.46-0.83) and 0.86 (0.78-0.90), respectively. Inverse correlations (Spearman rho) existed between Cystatin A and the rate of follicular fragmentation (rho = -0.658) and HIV-1 p24 antigen expression (rho = -0.622) in germinal centers and the amount of HIV-1 RNA in tonsillar tissue (rho = -0.765). The Cystatin A fraction declined from early chronic HIV-1 infection and was significantly lower in patients with a CD4 count below as compared with above 300 cells/muL of blood (P < 0.001), suggesting a favorable initiation of highly active antiretroviral therapy (HAART) at this level. Regeneration of Cystatin A to normal levels was shown in 11 patients 12 and 48 weeks after initiation of HAART, whereas the rate of follicular fragmentation was still elevated. Thus, we found Cystatin A to be a sensitive marker during HIV-1 infection and for regeneration of follicular lymphoid tissue during HAART.