Case reports and in vitro testing suggest sensitivity of malignant rhabdoid tumor of the kidney (MRTK) to anthracyclines. Prospective study data supporting doxorubicin's efficacy is lacking. We compared the change of tumor volume in the kidney to upfront treatment with either actinomycin D and vincristine (AV) or doxorubicin-intensified AV (AVD) in all patients with MRTK, who had been treated from 1991-2013 in Austria, Switzerland, and Germany in the framework of three prospective Société International d'Oncologie Pédiatrique/Gesellschaft für Pädiatrische Onkologie und Hämatologie nephroblastoma studies. A total of 37 patients with MRTK received pre-operative chemotherapy (AV, n = 19; AVD, n = 18). Initial and tumor volume after pre-operative treatment was reported in all patients who received AV and 15 of 18 (83%) patients who received AVD. Mean tumor volume at diagnosis was 247 (±48) mL in the AV cohort and 345 (±47) mL in the AVD cohort. Mean volume at surgery was 249 (±46) mL and 137 (±27) mL, respectively. Relative change in tumor volume was +19 (±16)% in patients who received AV and -63 (±26)% in patients who received AVD (P < 0.001). Change in volume to AV ranged from -60 to +224%, whereas the change to AVD ranged from -9 to -92%. We provide good evidence of doxorubicin's activity in MRTK in vivo by demonstrating a significantly better response to neoadjuvant AVD compared with AV alone.