BACKGROUND Several in vitro studies have reported on the efficacy of combined liposomal encapsulated doxorubicin (Doxil or Caelyx, MedEquip, UK) and hyperthermia over Doxil alone. OBJECTIVE To document the beneficial effect of Doxil-HT over Doxil alone in mice and to investigate the length of time HT should be delivered. METHODS M/109 lung tumor cells were injected into both leg pads of Balb/c female mice at age of 6-7 weeks. Two weeks later i.v. Doxil in a dose of 8 mg/kg (20-25 micrograms per mouse) was given and 4 HT sessions (2-3 days apart) were delivered during the subsequent 2 weeks at 2-3 days apart. HT was given to the left pad only for either 5 or 30 minutes (HT5 and HT30 respectively). Five weeks after tumor injection the mice were sacrificed and tumor volume and weight in both pads were measured. Internal comparisons between mice in the same treatment group and comparisons between different treatment cohorts were performed. RESULTS In the combined Doxil-HT5 and Doxil-HT30 cohorts the tumor volume and weight in both pads were similar and did not differ from those achieved by Doxil alone. In the Doxil-HT30 cohort the tumor weight, but not the tumor volume, were smaller than those in Doxil-HT5 and Doxil alone (P = 0.006 and 0.01 respectively). CONCLUSIONS The combined Doxil-HT30 treatment is more effective then Doxil-HT5 or Doxil alone. Additional studies with different time scheduling and different temperatures are warranted.