Reactive changes in intracellular free zinc ([Zn²⁺]_int) were monitored, using the fluorescent probe Zinquin, in human lymphoma cells exposed to the DNA damaging agent VP-16. Two-photon-excitation microscopy showed that Zinquin-Zn²⁺ complexes in cytoplasmic vesicles. [Zn²⁺]_int increased in both p53^wt and p53^mut cells after low drug doses. In p53^mut cells, non-competent for DNA damage-induced apoptosis, elevated [Zn²⁺]_int was maintained at higher drug doses, unlike competent p53^wt cells that showed a collapse of the transient prior to apoptosis. In p53^wt cells the [Zn²⁺]_int rise paralleled an increase in p53 and bax:bcl-2 ratio but preceded an increase in p21^WAF1, active cell cycle arrest in G2 or nuclear fragmentation. Reducing [Zn²⁺]_int , using TPEN, caused rapid apoptosis in both p53wt and p53^mut cells although co-treatment with VP-16 exacerbated apoptosis only in p53^wt cells. This may reflect changed thresholds for pro-apoptotic caspase-3 activation in competent cells. We conclude that the DNA damage-induced transient is p53-independent up to a damage threshold beyond which competent cells reduce [Zn²⁺]_int prior to apoptosis. Early stress responses in p53^wt cells take place in an environment of enhanced zinc availability.