The interaction of hyperthermia (HT) 1 hour at 44.0 degrees C and cyclophosphamide (CP) 200 mg/kg was studied in vivo in a solid transplantable neurogenic rat tumor (BT4A) in the foot of BD IX rats. HT was given by water bath heating. When both modalities were close in time (CP immediately before HT or 1 hour before HT), an enhanced effect with complete regression and cure of tumors was seen. This could not be obtained with either modality alone. Extending the interval between treatments within 24 hours, an effect equal to the sum of each modality was obtained when HT was given before CP, while HT after CP was less effective. Timing and sequence may be critical factors for the optimal combination of HT and cytotoxic drugs.