Background: Preoperative fluoropyrimidine based CRT is standard treatment in LARC patients. The aim of this study was to evaluate prognostic and predictive role of clinical and pathological factors in this setting Methods: Between December 2001 and January 2012 we evaluated 149 pts with cT3-T4 N-/+ rectal adenocarcinoma located ≤12 cm from the anal margin. Preoperative CRT consisted of radiotherapy 50.4 Gy in 28 daily fractions + 5-fluorouracil or capecitabine +/- oxaliplatin. Rectal surgery with total mesorectal excision was performed 6-8 weeks after the end of neoadjuvant treatment. Pathological examination of surgical specimens included TRG according to the Dworak criteria. TS, EGFR, Ki-67, p53, Bcl-2, MLH1 and MSH2 were immunohistochemically determined in pre-treatment biopsies and surgical specimens. For immunohistochemistry evaluation serial sections of formalin-fixed, paraffin-embedded tissues were stained with specific antibodies using a biotin-free ready-to-use amplification system Results: After a median follow-up of 60 months (2-122) we observed 4.7% local recurrences, 12.7% distant recurrences, and 13.4% deaths. In surgical specimens TRG 1, 2, 3 and 4 were observed respectively in 22.5%, 35.3%, 25.6% and 16.6% of patients. ypN and TRG were independent prognostic factors of DFS (p=0.020, p=0.027). CRM and TRG were independent prognostic factors of OS (p=0.016, p=0.010). High pre-treatment biopsy expression of TS was associated with poor TRG (0-1) (p=0.007); high biopsy expression of Ki-67 was associated with good TRG (2-4) (p=0.039); decrease between pre-treatment biopsy and surgical specimen of Ki-67 (Δ Ki-67 ≥ 0) was associated with good TRG (2-4) (p=0.02). Decrease in Ki-67 (Δ Ki-67 ≥ 0) was associated with good DFS (p=0.011) and confirmed by multivariate analysis as an independent prognostic factor (p=0.035). Conclusions: In our analysis ypN, CRM and TRG were independent prognostic factors; baseline expression of TS, Ki-67 and decrease in Ki-67 were predictive of TRG; decrease in Ki-67 was an independent prognostic factor of DFS.