Background: Treatment of patients (pts) with advanced penile SCC is very often unsuccessful. Single agents or combination therapies (Rx) combined with surgery achieved unsatisfactory results. We evaluated TPF in either neoadjuvant (NA), adjuvant (A) or metastatic (M) setting in a single-center pilot trial. Methods: 3-4 courses of paclitaxel 120 mg/m2 d1 or docetaxel 75 mg/m2 d1 + cisplatin 75 mg/m2 d1 + 5-fluorouracil (5FU) 96 hrs continuous infusion 750 mg/m2 from d1, q3wks were provided. Primary endpoint (EP) was progression-free survival (PFS). Safety profile, RECIST v.1.0 response rate (RR) and overall survival (OS) were the secondary EP. Results: From 7/2004 to 12/2010, 40 consecutive pts were treated, 34 of them fully evaluable for response and outcome. 8 pts underwent paclitaxel-PF and 26 docetaxel-PF. Grade ≥ 3 renal and neurotoxicity were recorded in 1 patient each. Adjuvant setting: 16 pts (4 bilateral and 14 pelvic pN2-3) underwent adjuvant TPF. Median PFS and OS were 7 mos (IQR 4-9) and 9.5 mos (IQR 4-17.5). 11 (69%) are alive after 7 mos (IQR 4-21.5) of median follow-up (f-u). No difference was recorded according to bilateral or pelvic disease. Neoadjuvant setting: 12 pts with cN2/3 M0 SCC (9 cN3) were treated. 4 of them (33%) had a nodal relapse after prior lymphadenectomy. Median PFS was 5 months (IQR 2-7.2). Three pts achieved a complete response (CR) and 4 pts achieved a partial response (PR, response rate-RR=58%). OS was 5 mos (IQR 2.7-9.2). 11/12 pts underwent surgery which was radical in 9 (75%). 2 pathologic-CR (17%) have been achieved. 6 pts (50%) are alive after a median f-u of 4.5 mos (IQR 2.5-6). Metastatic setting: 6 patients were treated. One (17%) had a PR and all died of disease. Median PFS and OS were 2 mos (IQR 1.2-2.7) and 5 mos (IQR 4.3-7.3). Median PFS and OS in the whole series were 6 (IQR 4-8) and 6.5 mos (IQR 3-12) respectively. Conclusions: Perioperative TPF showed activity in advanced penile SCC. It deserves further investigation in earlier disease stages (cN1-2), combined with surgery. An expansion cohort in NA setting is ongoing. Neoadjuvant TPF allowed to obtain a significant number of responses and to perform radical surgery even in nodal relapses after prior intervention.