Elevations in the levels of unsaturated fatty acids (FAs) in membrane lipids lead to an increase in cell membrane fluidity and may also be involved in cell fusion and death through the loss of normal membrane function and integrity. Since the infection of susceptible cells with HIV leads to cell fusion and subsequent loss of viability, the present study was undertaken to see whether HIV infection can alter the relative content of unsaturated FAs in the host cell membrane and to determine whether this change correlates with cell death. Peripheral lymphocytes (PBLs) of a healthy donor and two CD4+ cell lines were chosen: MT-4, which is killed following HIV infection, with significant cell death being observed 5 days postinfection, and H9 which is not killed. Measurements of FA content of the two cell lines and PBLs, either before or at 6, 24, and 48 h after infection, showed a significant rise in the concentration of unsaturated FAs followed by a drop in the concentration of saturated FAs in the MT-4 cell line. With regard to the H9 cell line similar results were obtained at 6 h from infection. However, at 24 and 48 h the concentrations of saturated FAs returned to preinfection levels while the concentrations of unsaturated FAs dropped to levels even lower than those obtained at zero time. No significant changes in FA composition were found with PBLs.