The effects of microwave induced hyperthermia, papaverine, and chemotherapy were evaluated in transplanted CI300 murine neuroblastoma. One hundred forty-five Ajax mice received axillary subcutaneous implants of CI300 round cell neuroblastoma (1.25 X 10(6) cells). Animals were divided into 8 treatment groups: Group 1 (n = 14) received no therapy (controls); Group 2 (n = 20) received radiofrequency microwave hyperthermia (2450 MHz at 40 milliwatts/cm2 for 4 min at 41.5 decrees C); Group 3 (n = 14) received papaverine (65 mg/kg for 3 days); Group 4 (n = 14) received a single intraperitoneal injection of cyclophosphamide (CPM) (50 mg/kg) and vincristine (VCR) (0.2 mg/kg); Group 5 (n = 22) received papaverine, cyclophosphamide, and vincristine as above; Group 6 (n = 20) received hyperthermia and papaverine; Group 7 (n = 18) received hyperthermia, cyclophosphamide, and vincristine; and Group 8 (n = 19) received hyperthermia, papaverine, cyclophosphamide, and vincristine. Therapy was instituted at 21 days after implant (tumor size 1 cm2), continuing for 2 weekly cycles. Animals were assessed for tumor regression, survival and relapse free rate at 1 and 4 wk. Tumor regression was seen only in animals receiving chemotherapy. Initial response rate (1 week) was 50% (group 4), 55% (group 5), 89% in (group 7), and 100% in mice receiving chemotherapy, papaverine, and hyperthermia (group 8) (p less than 0.05 7 and 8 versus 4 and 5). At 4 wk however, tumor relapse was noted in 6 of 7 group 4 responders, 10 of 12 in group 5, 13 of 16 in group 7, but only 4 of 19 group 8 responders (p less than .001 group 8 versus 4, 5, 7). These data indicate a synergistic effect of papaverine, microwave induced hyperthermia and chemotherapy in murine neuroblastoma. These observations suggest such treatment may be useful in clinical instances of neuroblastoma, especially in nonresponders to conventional therapy.