Non-Hodgkin Lymphoma (NHL) arising from the ear, nose, and throat (ENT) region presents unique challenges with regard to diagnosis and treatment. This study investigated the clinical characteristics, prognostic factors, and relapse patterns in patients with NHL originating from lymph nodes (nodal NHL) or other extranodal structures, aiming to identify factors associated with relapse between these two groups. This prospective cohort study included 50 patients diagnosed with NHL in the ENT region at a tertiary hospital in South-Western Romania between 2019 and 2021. Patients were categorized as having nodal or extranodal disease based on histopathological examination and were followed for three years to assess disease evolution, including relapse. Cox proportional hazards regression analysis was employed to identify factors associated with relapse-free survival. Extranodal NHL was associated with a significantly higher prevalence of multiple-site involvement compared to nodal NHL (53.3% vs. 30%, P = 0.021). While a trend towards increased relapse was observed in extranodal NHL, this was not statistically significant (P = 0.125). The presence of disseminated disease (HR = 27.295; P < 0.001) and undergoing only a biopsy (compared to total excision, HR = 4.301; P = 0.027) were identified as independent predictors of relapse. Kaplan-Meier analysis demonstrated significantly different relapse-free survival patterns among groups stratified by NHL localization and dissemination status (P < 0.001). The extent of surgical intervention is a crucial factor influencing relapse risk in ENT NHL, with total excision associated with a lower hazard of relapse. At the same time, extranodal involvement may indicate a more aggressive disease course, particularly when combined with dissemination. However, larger studies with longer follow-ups are needed to validate these findings and refine treatment strategies, especially in regions with limited access to healthcare and screening programs.