The time course and extent of thermal ablative injury differs in liver compared to tumour tissue. This may be influenced by differences in the expression of heat shock proteins (HSP) and the response of Kupffer cells to thermal injury. This study determines the expression and response of HSP70 and Kupffer cells to thermal ablative injury in a Murine model of colorectal liver metastases. Thermal ablation by laser (Nd-YAG wavelength 1064 nm) was induced in liver and colorectal cancer liver metastases in CBA strain mice. Laser energy was applied at 2 W for 50 s and produced incomplete tumour ablation. Established tissue injury was assessed in separate groups of animals at time points ranging from 12 h to 21 days following therapy. HSP70 and Kupffer cell expression at the margins of coagulated tissue was determined by immunohistochemical staining for HSP70 and F4/80 antigens, respectively. HSP70 was faintly expressed in the cytoplasm of all tumour cells, with distinct clusters exhibiting intense cytoplasmic and nuclear HSP70 staining (130+/-19 cells mm-2). Comparatively, HSP70 expression was uncommon in untreated control liver specimens (2+/-2 cells mm-2, p<0.001). Thermal ablation increased expression of HSP70 at coagulated tissue margins. The peak response in tumours occurred at 2 days post-ablation and was significantly greater than the peak response in liver, occurring at 12 h (809+/-80 cells mm-2 vs. 454+/-52 cells mm-2, p<0.001). HSP70 expression remained significantly elevated for 7 days following therapy in tumour tissue, compared to 3 days in liver. Kupffer cell numbers in untreated control tumours were significantly lower than in untreated control livers (285+/-23 cells mm-2 vs. 451+/-30 cells mm-2, p<0.001). Following thermal ablation, there was an initial decrease in Kupffer cell numbers at the margin of coagulation with subsequent persistent increases thereafter. In liver tissue, the peak Kupffer cell response occurred at 5 days post-therapy and was significantly greater than the peak response in tumour tissue 3 days post-thermal ablation (1074+/-34 cells mm-2 vs. 860+/-53 cells mm-2, p=0.007). Thermal ablation produces a greater and more prolonged HSP70 response in colorectal liver metastases than in liver tissue. It also induces persistent increases in Kupffer cell activity in liver and tumour tissue.