Surgically resected epidermal growth factor receptor-mutated non-small cell lung cancer continues to carry a substantial risk of recurrence. The aim of this retrospective, single-center study, conducted at a Portuguese tertiary hospital was to evaluate the clinical course of these patients, diagnosed between 2016 and 2020, with the final clinical data review in November, 2024. A total of 48 patients were included, predominantly female (72.9%) and non-smokers (70.8%), most presenting exon 21 L858R or exon 19 deletion mutations. Mutations were identified by Sanger sequencing or next-generation sequencing. Programmed death-ligand 1 expression was < 1% in 58.3% of cases. At a median follow-up of 73.6 months, 31.3% of patients experienced relapse, all progressing to stage IV disease. The five-year disease-free survival and overall survival rates were 70% and 81%, respectively. Staging significantly influenced prognosis, with five-year disease-free survival ranging from 84% in stage IB to 20% in stage III. No significant differences were observed between epidermal growth factor receptor mutation subtypes. These findings are consistent with previous real-world studies and the placebo arm of the ADAURA trial, supporting the use of adjuvant osimertinib to reduce recurrence and improve long-term outcomes, while also emphasizing the need for improved perioperative risk assessment – including staging, histopathologic features, and molecular and genetic profiling – to guide personalized treatment.