Chemotherapeutic cytoreduction of soft tissue sarcomas may permit less radical operation. In cases of large or multi-compartmental masses, deeply seated tumors or involvement of a neurovascular bundle, down-sizing of the mass is required before limb sparing surgery can be considered. We have applied a combination chemotherapy consisting of intravenous adriamycin and ifosfamide with intra-arterial cisplatin for patients with soft tissue sarcomas of the extremity as induction treatment, and switched to an intravenous-only protocol due to toxicity and management difficulties. Adjuvant chemotherapy and radiation therapy were given after limb-sparing surgery in both regimens. Fresh tumor specimens were obtained and were examined for tumor size, surgical margins, percent of necrosis, evidence of vascular or perineural invasion, and the presence of Pgp, Ki-67, p53, PCNA and bcl-2-oncoprotein. Our results in terms of percentage of tumor necrosis were comparable and even better in favor of the second regimen [38% good histological response with intravenous (i.v.)-only versus 12.5% for combined i.v. + intra-arterial (i.a.]. The clinical and radiological responses were also better for the second (i.v. only) regimen (45%) than for the first (i.v. + i.a.) regimen (12.5%). The toxicity and the inconvenience to the patients and to the treating staff were greater in the first regimen that combined intra-arterial and intravenous infusions. In the first group the failure rate is 75% within 32 months of follow-up, while it is 33% within 12 months follow-up in the second group. The immunohistochemical markers did not correlate with disease control nor with the patient outcome. Intravenous administration of ADR-IFX induction chemotherapy was more feasible than combined i.v. ADR-IFX plus i.a. cisplatin and achieved better results.