Background: Squamous cell carcinoma (SCC) arising from paranasal sinus and nasal cavity (PNSNC) is often diagnosed at locally advanced stage. Neoadjuvant strategies have been explored to improve prognosis and facilitate organ preservation. The efficacy of triplet neoadjuvant chemotherapy (NAC) has not been established prospectively. We conducted a phase II trial of neoadjuvant docetaxel/5-FU/cisplatin (DFP) combined with prophylactic pegteograstim in unresectable, locally advanced PNSNC (KCT0003377). Methods: Eligible patients had unresectable SCC of PNSNC, were aged 19-75, had an ECOG performance status of 0/1, and demonstrated adequate organ function. Patients with distant metastasis were excluded. Criteria for unresectability included tumor or lymph node fixation, clinical T3/4 stage, or potential compromise of critical organ function (e.g., necessitating eyeball exenteration). NAC comprised three cycles of docetaxel (75mg/m2 on Day 1), cisplatin (75mg/m2 on Day 1, 60mg/m2 for those aged ≥65), and 5-FU (1,000mg/m2 on Days 1-4) administered every 3 weeks. Prophylactic pegteograstim (6mg) was administered on Day 6 or 7. The primary outcome was the overall response rate (ORR), with secondary outcomes including progression-free survival (PFS), the eyeball preservation rate at 24 months, and safety. The study required 28 patients to achieve a power of 80% (P0=0.45, P1=0.70, α-error=0.05, 10% dropout rate). Results: Between 2019 and 2023, 28 patients were screened, and 27 received at least one cycle of NAC. The median age was 58 years (range: 41-71), with 24 males. Seventeen had maxillary sinus origin, and ten had nasal cavity origin. Twenty-two patients had T4 disease, and six had N2 disease. The ORR was 64.3% (5 complete responses, 13 partial responses). Post-NAC treatments included surgery alone (n=2), concurrent chemoradiotherapy (CCRT) (n=15), surgery followed by CCRT (n=2), or radiotherapy (RT) (n=5). Procedures performed were total maxillectomy (n=4), partial maxillectomy (n=3), and endoscopic sinus surgery (n=2). With a median follow-up of 21.5 months (range: 0.1-53.0), the 2-year PFS and eyeball preservation rate were 64% and 100%, respectively. Fourteen patients experienced Grade ≥3 adverse events (AEs): hematologic (46.4%), non-hematologic (14.3%), with Grade 3/4 neutropenia (32.1%) and febrile neutropenia (14.3%). Dose reduction or delay occurred in 9 patients (33.3%). One patient died on Day 6 of cycle 1. Conclusions: DFP NAC demonstrated promising efficacy and an excellent eyeball preservation rate with manageable toxicity. DFP NAC with prophylactic pegteograstim, could be a reasonable option for patients with locally advanced SCC of the PNSNC. Follow-up is ongoing. Clinical trial information: KCT0003377.