The Study was undertaken to evaluate the heat resistance by split dose hyperthermia in various time interval and temperature. For the experiments, 96 mice were divided into 2 groups : the first, 36 mice were used to evaluate the skin reaction of mouse tail to single dose hyperathermia, the second, 60 mice were used to evaluate heat resistance by split does hyperthermia in various time intervals. The results obtained are summarized as follows : 1. The ND50 was 101 minutes at 43$^{circ}C$ and 24$^{circ}C$ minutes at 45$^{circ}C$. 2. For a 1 increase in temperature, a half in time was required to same degree of skin reaction. 3. Heat resistance was significantly developed in split dose hyperthermia at 43$^{circ}C$ and 45$^{circ}C$. 4. Development, maximum and decay of heat resistance were constant regardless of change in temperature. In summary, heat resistance in split dose hyperthermia is important is study and clinical application of heat therapy in maligant disease.