When CHO cells were exposed to hyperthermia and subsequently to photodynamic treatment, the combined effects were additive but in the reverse sequence the interaction was synergistic. The synergistic interaction comprised two quite different components: (1) photodynamically induced sensitization of cellular proteins and/or supramolecular structures for thermal inactivation and (2) a photodynamically induced inhibition of the cellular repair system for sublethal thermal damage. The first component of the synergistic interaction was reflected by a change of the Arrhenius parameters of thermal cell killing. A lowering of the activation energy of this process was responsible for the synergistic interactions, whereas a concomitant decrease of the frequency factor, opposing this effect, actually caused a much lower degree of synergism at higher temperatures. This component of the synergistic interaction did not respond to the insertion of an intermediate incubation period between the two treatments. The second component of the synergistic interaction, viz the interference with the ability of cells to survive sublethal thermal damage, was reversible, as an intermediate incubation between photodynamic treatment and hyperthermia resulted in its repair. The photodynamically induced inhibition of the ability of cells to survive sublethal thermal damage was not related to ATP or glutathione depletion, inhibition of de novo protein synthesis or impairment of degradation of damaged protein molecules. Restoration of the repair system for sublethal damage depended on a metabolic process and required free intracellular Ca2+, suggesting that a cell signaling pathway may be involved. Thus, in a practical sense the magnitude of the synergistic interaction between photodynamic treatment and hyperthermia depends on the length of the interval between the two treatments and on the temperature and duration of the subsequent thermal treatment. This may have significant consequences for the development of clinical protocols for the combined application of photodynamic therapy and hyperthermia in the treatment of tumors.