Infection with HIV causes a reduction in the numbers and function of CD4+ lymphocytes and functional abnormalities of other cells. We have studied the effect of HIV infection on signal transduction in the H9 lymphoblastoid CD4+ cell line. Resting HIV-infected H9 cells show evidence of chronic activation with raised levels of lnsP3and lnsP4, the active metabolites of the inositol polyphosphate pathway, and a consequently raised intracellular free calcium concentration. Stimulation of HIV-infected H9 cells with phytohernagglutinin (PHA) leads to a fall in the previously raised levels of lnsP3but a further rise in lnsP4, whilst an attenuated intracellular calcium rise is seen with both PHA and anti-CD3 antibody. The observed effects of HIV infection on signal transduction provide a mechanism to explain the functional defects in CD4+ lymphocytes and, possibly, other cell types.