Tumor necrosis factor (TNF), a peptide produced by macrophages with cytostatic and cytolytic effects, demonstrated single agent antitumor activity and synergistic effect when administered with dactinomycin in in vitro tumor cell lines, in vivo xenograft models, and adult and pediatric phase 1 clinical trials. This phase 2 pediatric trial evaluated the efficacy and further defined the toxicity profile of recombinant TNF (rTNF) and dactinomycin in patients with recurrent or refractory Wilms tumor. On this 2 stage Children's Cancer Group trial, dactinomycin (15 microg/kg/d, IV) immediately followed by rTNF (200 microg/m/d, IV), once daily for 5 consecutive days, was administered to patients with recurrent or refractory Wilms tumor. Cycles repeated every 21 days to a maximum of 12 courses. Nineteen of 21 consecutive patients, ranging 0.9 to 16.5 years of age at the time of initial diagnosis, were evaluable for response and toxicity. Three patients (15.8%) had a complete response, 5 (26.3%) had stable disease, and 11 (57.9%) had progressive disease. Following 59 patient treatment cycles, the most commonly observed grade 3/4 toxicities were thrombocytopenia (40.7%), elevated liver transaminases (23.7%), neutropenia (20.3%), leucopenia (13.6%), anemia (11.9%), and myalgias (10.2%). Before completion of stage 2, the study closed due to unavailability of rTNF. The documented complete responses and disease stabilization suggest antitumor activity of rTNF with dactinomycin in patients with recurrent Wilms tumor. The combination was well tolerated. Although grade 3/4 adverse events were reported, dose adjustments were not required. Toxicities resolved without significant interventions.