Changes in active K+ and Na+ influx during the cell cycle of neuroblastoma (clone Neuro-2A) have suggested activation of an Na+, H+ exchange system during the G1/S-phase transition. Here we report that pHi, measured by the digitonin null-point method, is constant during G1-phase and the G1/S-phase transition and decreases in early S-phase. In addition pHi is shown to be most sensitive to the diuretic amiloride in the G1/S-phase transition, in agreement with the ion influx data. It is concluded from these data, that pHi is tightly regulated during the early cell cycle phases by the Na+, H+ exchange system, in particular during the G1/S-phase transition.