Background: Neoadjuvant chemotherapy for locally advanced soft tissue sarcomas, although not standard, represents a promising option for resectable tumours. The discovery of biological predictors of chemotherapy response highlights the possibility to develop individualised therapeutic approaches in selected group of patients or predict survival also. The SMAD4 protein, a member of TGFβ superfamily has a role in progression and tumor metastasis and may be involved sarcomas recurrence. Methods: 30 patients with soft tissue sarcomas (STS) of high-grade located in extremities treated with neoadjuvant doxorubicin and ifosfamide chemotherapy were observed prospectively since January 2005 to June 2011. All patients were submitted to radiation therapy adjuvant. Surgical specimens after neoadjuvant treatment were evaluated of SMAD4 nuclear expression by immuno-histochemistry and percentage of viable cells Results: The median follow-up time was 42 months. The overall survival (OS) was 91.7% in patients with low expression SMAD4 nuclear protein associated with ≤10% of viable cells (n=12) in the surgical specimen and 68.9% in the remaining patients. Likewise, the disease free survival (DSF) was 91.7% versus 38.6% (p 0.01) respectively. Conclusions: The combination of nuclear SMAD4 low expression and 10% or less of viable cells in the surgical specimen was statistically significant in better DFS in patients with locally advanced extremity STS treated with neoajuvant chemotherapy with benefit in OS.