Background: Laryngeal Squamous Cell Carcinoma (LSCC) is a commonly occurring malignancy in the head and neck region. However, due to the heterogeneity of primary tumor sites, tumor behavior, and molecular mechanisms, there is currently no consensus on the accuracy of clinicopathological prognostic factors for individual cases. Tumor histopathologic behavior remains a crucial factor in predicting aggressiveness. Recent studies have shown that peritumoral tumor budding (TB) combined with cell nest size (CNS) is a reliable marker for predicting lymph node metastasis, advanced cancer prognosis, and therapeutic response in SCCs of different origins. Materials and methods: In this retrospective cross-sectional study, we analyzed 128 LSCC cases that underwent total laryngectomy at Amir Alam Hospital. We evaluated TB and CNS based on the Boxberg et al. study. Results: Our study demonstrated a significant correlation between TB, and nodal involvement (P value=0.015), vascular invasion (P value=0.035), and mortality rate (P value=0.001), as well as a significant statistical correlation between high TB and extra-laryngeal extension (P value=0.006), clinical stage (P value=0.011), and mortality rate (P value=0.001). Moreover, small nest size was also associated with the clinical stage (P value=0.047), extra-laryngeal extension (P value=0.015), and mortality rate (P value=0.001). Based on our results, TB, CNS, and clinical stage are independent prognostic factors for mortality rate and are correlated with disease-free survival. Conclusion: Given the effect of TB and CNS on the overall prognosis and survival of patients with LSCC, evaluating these two factors on routine H&E microscopic examination of LSCC specimens is recommended to facilitate individualized risk assessment and treatment planning.