Background: Survival outcomes for elderly non-Hodgkin’s lymphoma (NHL) patients are disproportionally inferior to those of younger patients. While their tumor biology may differ, elderly patients are often frail with comorbidities and polypharmacy, and use potentially inappropriate medications (PIM) as defined by the Beers Criteria. Methods: Using Cox proportional hazard and logistic regression models, we retrospectively analyzed all NHL patients age 60 and above diagnosed at our institution from 2009-2014 to examine the impact of polypharmacy and PIM use on primary end-points of progression-free survival (PFS) and overall survival (OS), and the secondary end-point of treatment-related toxicities. Results: We included 246 patients with evaluable data after excluding patients with incomplete record or treated elsewhere. The median age was 71 years. Aggressive lymphoma accounted for 57% of patients. At the time of diagnosis, 49% of patients had more than 4 medications and 48% used at least one PIM. During first-line treatment 45% of patients experienced grade 3 or greater toxicities (CTCAE v4). Charlson Comorbidity Index (CCI), polypharmacy, and PIM use correlated with each other. Number of medications (p = 0.004) and PIM use (p < 0.001) were associated with shortened PFS by log-rank test, and PIM use remained an independent predictor of PFS in multivariable analysis (HR 1.62, p = 0.001). Number of medications (p = 0.004) and PIM use (p = 0.002) were also associated with shortened OS by log-rank test. However, only CCI and lymphoma grade predicted OS in multivariable analysis. Finally, PIM use was strongly associated with grade 3 or greater toxicities in multivariable analysis (OR 3.1, p = 0.002). Conclusions: We report here for the first time adverse impact of geriatric polypharmacy and PIM use in elderly lymphoma patients. It seems plausible that the reduced survival is due to drug-drug interactions during intensive chemotherapy that lead to increased toxicities or impair delivery of full dose chemotherapeutics. Our findings support the use of geriatric principles to guide meticulous medication management to improve outcomes for elderly lymphoma patients during active treatment.