The combination of biological response modifiers with cytotoxic drugs has proven to be synergistic in several tumor systems. Recombinant human tumor necrosis factor (rhTNF) has been shown to enhance the antitumor efficacy of etoposide (VP-16) in the treatment of C1300 murine neuroblastoma. However, after completion of therapy, tumor growth resumes and results in subsequent death. In an effort to assess the impact of combining surgery with rhTNF/VP-16 therapy, A/J mice bearing the C1300 murine neuroblastoma were treated within adjuvant or neoadjuvant protocols. Adjuvant-treated animals had a longer interval to disease recurrence (P = .01) and smaller average recurrent tumor volumes postexcision (P less than .05) compared with surgical controls. Histological evidence of tumor recurrence and liver metastases was seen in both adjuvant-treated and surgical control animals. Neoadjuvant-treated animals had a longer interval to disease recurrence (P = .03) and smaller average recurrent tumor volumes up to 14 days postexcision (P less than .02) compared with surgical controls. In addition, 30% of the neoadjuvant-treated animals had no microscopic evidence of disease recurrence, and only 14% had histological evidence of liver metastases. The surgical controls in the neoadjuvant experiment all had histological evidence of disease recurrence and liver metastases. Thus, the combination of surgery and rhTNF/VP-16 in the adjuvant or neoadjuvant setting appears to significantly delay the progression of C1300 murine neuroblastoma. Furthermore, administering chemoimmunotherapy prior to surgical excision in a neoadjuvant manner appears to be most beneficial as regards prevention of local disease recurrence and distant metastases.