Background: The standard of care for metastatic or unresectable head and neck squamous cell cancers (HNSCCs) is 5-FU and a platinum doublet with cetuximab or pembrolizumab. However, these regimens are cumbersome as they involve hospitalization for continuous 5-FU infusion and carry a high toxicity profile. In addition, many patients are unfit for this regimen due to poor performance status (PS) or comorbidities. An alternative is paclitaxel, carboplatin, and cetuximab (PCC). PCC has been shown to be a promising induction regimen in small, mostly retrospective studies. Also, low dose chemotherapy may improve tolerability. Our study evaluates the tolerability and efficacy of low dose PCC with or without concurrent palliative radiation therapy (RT) in patients with metastatic or unresectable HNSCCs. Methods: This retrospective observational study included 40 patients with metastatic or unresectable HNSCCs at a single academic center who received PCC between August 2017 and January 2022. Included patients were not candidates for standard frontline therapies due to either PS, comorbidities, prior progression on these therapies, plan for RT, or patient preference. Chart review was performed to grade adverse events (AEs) according to CTCAE criteria. Progression free survival (PFS), overall survival (OS), and response to treatment were assessed per RECIST 1.1 guidelines. Results: Of the 40 patients, mean age was 69.6 years (SD 15.4), and 82.5% were male. Common primary sites were oral (13, 32.5%), oropharynx (12, 30%), hypopharynx (4, 10%), and sinus (4, 10%). Most patients had Stage IVa disease (16, 40%) followed by IVc (12, 30%) and IVb (6, 15%). The remainder (6, 15%) had stage III or unknown stage. Patients received weekly paclitaxel (30-50 mg/m2), carboplatin (AUC 1.5-2), and cetuximab 400 mg/m2 loading followed by 250 mg/m2 maintenance dose. 8 patients (20%) received concurrent RT. Most were treated with palliative intent (32, 80%) and a few induction intent (8, 20%). Prior to PCC, 11 patients had prior salvage surgery, 19 prior RT, and 18 prior systemic therapy. Baseline ECOG PS was 0-2 in 37 patients (92.5%). The most common AEs were skin rash (27, 67.5%), fatigue (22, 55%), and mucositis (12, 30%). 7 patients (17.5%) experienced a grade 3-4 AE, which were mostly hematologic. 2 of the 8 patients on concurrent RT experienced a grade 3-4 AE. 5 patients (12.5%) stopped PCC treatment due to toxicities. 8 patients (20%) had progression on initial follow up imaging. Median duration of response was 4.3 months. PFS was 7.8 months. Median OS was 19.2 months. Conclusions: Our study supports the use of PCC in metastatic or unresectable HNSCCs. This regimen can be considered in patients with suboptimal PS who are not candidates for standard frontline therapies or for those planned for palliative RT. PCC can be used safely and effectively with or without concurrent RT.