Background: Head and Neck Squamous Cell Carcinoma (HNSCC) is a heterogeneous group of malignancies arising from the mucosal linings of the oral cavity, pharynx, and larynx. Locally advanced HNSCC (LA-HNSCC), encompassing stages III and IV, involves large tumors and regional lymph node metastases without distant spread, contributing to high morbidity and mortality. Understanding the clinical features of LA-HNSCC is crucial for improving treatment strategies and patient outcomes. Objective: To evaluate the clinical characteristics of patients with LA-HNSCC and their impact on treatment outcomes, specifically comparing the TPLF and LFP regimens. Methods: An experimental study was conducted at Khwaja Yunus Ali Medical College & Hospital from January to December 2015, involving 60 patients with LA-HNSCC. Patients were treated with neoadjuvant chemotherapy (TPLF or LFP regimens) followed by concurrent chemoradiation. Data was collected through patient interviews, clinical evaluations, and laboratory tests. The primary outcome measures were tumor regression, clinical response, and acute toxicities. Statistical analysis was performed using SPSS, with significance set at p < 0.05. Results: The majority of patients were male (80% in Arm A and 77% in Arm B) and over 50 years old. Smoking prevalence was high (83.3% in Arm A and 80% in Arm B). The most common primary tumor sites were the oral cavity (Arm A: 30%, Arm B: 33.3%) and oropharynx (Arm A: 23.3%, Arm B: 26.7%). Neck node swelling, pain, dysphagia, and weight loss were the most frequent clinical complaints. No statistically significant differences were found between the two treatment arms in terms of age, smoking, occupation, ECOG performance status, or histological grading. Conclusion: Both TPLF and LFP regimens provided similar outcomes in terms of clinical characteristics and treatment response in patients with LA-HNSCC. These results suggest that the choice between TPLF and LFP regimens may not significantly influence treatment outcomes. Further research is needed to explore additional factors affecting treatment efficacy and refine therapeutic strategies for LA-HNSCC.