Background: Bulky nodal metastases (N2-N3) of PSCC represent a negative prognostic factor, yet efficacy of multimodal treatment is not defined. For these patients (pts) we explore T-PF combination in adjuvant and neo-adjuvant setting. Methods: Paclitaxel (120 mg/m2, d1) or docetaxel (75 mg/m2 d1) plus cisplatin (75-100 mg/m2 d1) and 5-fluorouracil (5FU, 750-1000 mg/m2 96h d1) were scheduled prior to or following radical inguino-pelvic dissections in N2-3 M0 pts, according to protocol indications. Primary endpoints were overall (OS) and progression-free survival (PFS); safety and response-rate represented secondary endpoints. Association of survival with treatment setting and pre-specified covariates was explored. Results: From 6/2004 to 10/2012, 47 consecutive pts received neoadjuvant (N=28) or adjuvant (N=19) T-PF. 18 (38.3%) were disease-free after a median follow-up (FU) of 22 mos (IQR 17-42). Durable remissions were more frequently observed in adjuvant (52.6%; median FU: 42 mos) than in neoadjuvant group (28.6%; median FU: 17 mos). Distribution of OS and PFS were statistically in favour of adjuvant T-PF (p=0.01 at Wilcoxon test; p=0.008 at t test). However, Kaplan-Meyer curves did not show significant differences. A model including therapy setting, N category, laterality, pelvic extent and p53 status showed that only adjuvant administration was associated with improved OS (p=0.008), while adjuvant therapy (p=0.002), pelvic extent (p=0.029) and laterality (p=0.086) were associated with PFS. In neoadjuvant group we recorded 43% responses (complete [CR] and partial) and 4 (14%) pathologic CR. Surgery was possible in 18 (64.3%) pts, independently of response. Neither OS nor PFS were associated with response. Tolerability was mild to moderate. Conclusions: Adjuvant chemotherapy was the most important favourable predictor of OS and PFS. Adjuvant T-PF results are among the best available ones. Neoadjuvant T-PF compares with other recent schedules in terms of activity and efficacy. Surgery remains the mainstay treatment for resectable nodal metastases from PSCC.