Chinese hamster V79 cells were treated with photodynamic therapy (PDT) sensitized by aluminum phthalocyanine (AlPc) or with the ionophore nigericin or with combinations of PDT and nigericin. We previously showed that PDT and nigericin interact synergistically in the killing of these cells; i.e. doses of PDT that kill no more than 10% of the cells in combination with nontoxic exposures to nigericin lead to a loss of clonogenicity of three to five orders of magnitude. Photodynamic therapy induces an enhanced rate of expression of the stress gene grp-78 both at the transcriptional and translational levels and causes a decrease in the synthesis of the constitutive heat shock protein HSP-70 as well as in expression of HSP-70 mRNA. When the cells are exposed to PDT in the presence of nigericin, these effects are elicited at three- to four-fold lower PDT doses. Thus, PDT in the presence of nigericin is much more effective in inducing the changes in gene expression than is PDT alone. In the absence of nigericin the PDT dose inducing a two-fold increase in GRP-78 accumulation causes little or no loss of clonogenicity. In the presence of nigericin, however, the PDT dose leading to a similar change in GRP-78 level produces up to a 50% loss of clonogenicity. The fact that nigericin is dose-modifying for both cell killing and stress responses suggests that nigericin either increases the yield of oxidative damage from a given dose of PDT or magnifies the cellular response to a constant level of oxidative stress.