Abstract Background Although polypharmacy has been described among cancer patients, very few studies have focused on those with lung cancer. We aimed to assess whether polypharmacy and comorbidity have an impact on systemic parenteral treatment administration and survival among lung-cancer patients. Methods In this retrospective monocenter cohort study, we included patients hospitalized in thoracic oncology for the first time between 2011 and 2015. The Elixhauser score was used to assess comorbidity and polypharmacy was estimated with a threshold of at least five prescribed medications. The Fine and Gray competitive risk model was used to estimate the impact of polypharmacy and comorbidity on systemic parenteral treatment administration within the first two months of hospitalization. The effect of comorbidity and polypharmacy on overall survival was evaluated by Cox proportional hazards analysis. Results In total, 633 patients were included (71% men), with a median age of 66 years. The median Elixhauser score was 6 and median overall survival was four months. Among the patients, 24.3% were considered to be receiving polypharmacy, with a median number of medications of 3, and 49.9% received systemic parenteral treatment within two months after hospitalization. Severe comorbidity (Elixhauser score > 11), but not polypharmacy, was independently associated with a lower rate of systemic parenteral treatment prescription (SdHR = 0.4 [0.3;0.6], p < 0.01) and polypharmacy, but not a high comorbidity score, was independently associated with poorer four-month survival (HR = 1.4 [1.1;1.9], p < 0.01) Conclusions This first study to evaluate the consequences of comorbidity and polypharmacy on the care of lung-cancer patients shows that a high comorbidity burden can delay systemic parenteral treatment administration, whereas polypharmacy has a negative impact on four-month survival.