Acidosis is a well established concomitant of tissue ischemia. Acidosis in the pH range 6.0-7.0 is seen in cerebral ischemia and within solid tumors. Extracellular acidosis of pH 6.0 and 6.4 provided essentially complete protection from 48 h serum deprivation induced apoptotic death of cultured primary murine neurons. We tested the effect of p53 using transformed mouse embryo fibroblasts of either p53+/+ or p53-/- genotype. Both were markedly protected from serum deprivation by acidity. Hypoxia induced fibroblast injury was also reduced at pH 6.8. Lower pH resulted in a shift from apoptotic to necrotic morphology after 42 h hypoxia. Acidosis reduces apoptosis of both normal and transformed cells, irrespective of p53 status.