OBJECTIVE: Polypharmacy (PP) is a common problem among the older adults and has a potential effect on health-related problems. However, the significance of PP in older advanced non-small cell lung cancer (NSCLC) patients and those on oral molecular-targeted anticancer agents is unclear. MATERIALS AND METHODS: This retrospective, nonrandomized study reviewed the records of 334 advanced NSCLC patients who underwent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. PP was defined as ≥ 5 concomitant medications. Potentially inappropriate medication (PIM) use was measured using the updated screening tool of older people's prescriptions (STOPP) ver. 2 criteria. We also estimated survival distributions using the Kaplan-Meier method, compared between-group differences using the log-rank test, explored potential predictors of survival using Cox regression, and performed cluster analysis to identify factors affecting multiple-medication use. RESULTS: The PP and PIM use prevalence was 38.4% and 31.9%, respectively. The median overall survival (OS) for PP(+) and PP(-) patients was 19.4 and 27.3 months, respectively. Multivariate analysis revealed a significant correlation between PP and OS. The frequency of unexpected hospitalization during EGFR-TKI treatment was higher in PP(+) patients compared to PP(-) patients (49.4% vs. 29.4%; odds ratio = 2.34). CONCLUSION: PP is an independent prognostic factor in older advanced NSCLC patients taking EGFR-TKIs. PP can be used as a simple indicator of such patients' comorbidities and symptoms or as a predictive marker of unexpected hospitalization during treatment.