The aim of the present study was to assess the possibility that mCD38, a bifunctional ectoenzyme with NAD+ hydrolase and ADP ribose cyclase activities, exerts a protective role in the development of acute, non-syncytial cell death from HIV-1. This hypothesis was tested in a panel of human T-cell lines with defined membrane CD4 (mCD4) expression. A negative correlation was found between the levels of mCD38 expression and the rate of acute cell death from HIV-1 observed 96 h after infection. The negligible rate of cell death from HIV-1 detected in some cell lines (H9 and Supt-1) is apparently unrelated to the level of mCD4 expression, whereas the association with high levels of mCD38 is confirmed. In H9 and Supt-1 cells, the fraction of cells positive to HIV-1 p24 is lower than in the mCD38low cell lines (MT-4, MT-2, C8166). This suggests that high CD38 expression is correlated to resistance to HIV-1 infection, resulting in a lower rate of cell death. A further finding supporting the work hypothesis is that the addition of nicotinamide, a reaction product of CD38, confers to MT-4 cells (mCD38low) partial protection against acute cell death from HIV-1. This indicates that nicotinamide may be at least partially responsible for the correlation observed between high levels of mCD38 and negligible rates of acute cell death from HIV-1.