Purpose: Palbociclib, a CDK4/6 inhibitor, has shown radiosensitizing effects in preclinical studies. There is a strong rationale for adding palbociclib to cetuximab and radiotherapy in LA-HNSCC, especially in p16-negative HNSCC. Patients and Methods: We conducted a phase I dose escalation study (NCT03024489) using a classical 3+3 design to determine safety, tolerability, and maximum tolerated dose (MTD) of palbociclib, cetuximab, and IMRT combination. At the recommended phase 2 dose (RP2D), additional p16-negative patients were enrolled. Results: Twenty-seven LA-HNSCC patients (13 in dose escalation, 14 in expansion) with oropharyngeal (41%) and hypopharyngeal (30%) cancers, were enrolled. The MTD was not reached, and the RP2D of palbociclib was established at the full standard palbocilcib dose of 125 mg/day for 21 days per cycle, administered for 2 cycles during IMRT. The most common grade 3-4 toxicities were mucositis (59%), radiation dermatitis (22%), and neutropenia (22%), with a febrile neutropenia rate of 7%. Common genomic alterations included mutations in TP53 (57%), GNAQ (35%), and PIK3CA (17%), and copy number gains in CCND1 (22%), CCND2 (9%), and EGFR (9%). Overall, p16-expression was positive in 15% of patients. No correlation was observed between p16 status, genomic alterations, and preliminary efficacy. The objective response rate was 84%. The rates for two-year locoregional control, event-free survival, and overall survival were 73%, 48%, and 71%, respectively. Conclusions: The palbociclib, cetuximab and IMRT combination was well-tolerated. The RP2D was established, while no MTD was determined. The regimen demonstrated promising preliminary efficacy, suggesting further investigation is warranted in cisplatin-ineligible p16/HPV-unrelated LA-HNSCC patients.