Background Optimizing clinical selection of NSCLC patients expected to benefit from immune check-point inhibition (ICI) is necessary since only a minority of patients obtain durable long-term responses. Most NSCLC patients are > 70 years old with substantial tobacco-related comorbidity and thus exposed to polypharmacy (PP). Studies exploring PPs effect on response, long-term effect, and adverse events in NSCLC patients undergoing ICI are presently lacking. Methods Retrospective data from 118 patients with advanced or metastatic NSCLC initiating ICI (Nivolumab or Pembrolizumab) at a single-center from September 2015-April 2018 was gathered with data-cutoff at April 1st 2020. Baseline registration of PP (≥5 regular drugs), antibiotics and steroids (both within one month prior to ICI) and comorbidity according to Charlsons Comorbidity Score Index (CCIS) was performed. Immune-related Adverse Events (irAEs) were registered prospectively. Kaplan-Meier, logistic regression, and cox regression data analyses were performed. Results All patients had completed ICI at time of follow-up (FU) with a median FU of 40.8 months (range 0.4-51). In multivariate survival analysis (including factors of age, CCIS, disease stage, line of treatment and performance score) median OS in the group of PP was 7.0 months compared to 24.1 months in the non-PP group (HR 2.45, p=0.001, CI 1.42-4.21). Median PFS in the PP group was 2.0 versus 7.9 months (HR 2.20, P=0.002, CI 1.35-3.60). PP correlated to radiologic response (p=0.046). Antibiotics, prior to ICI was a negative predictor of OS and PFS. Steroid use prior but not during ICI was a negative predictor of OS. A significantly higher number of patients with PP had irAE grade 3-4 at the time of ICI termination. Conclusions Evaluation of PP prior to ICI might aid clinical treatment decisions on ICI in NSCLC patients. Potential drug-interactions and risk of non-benefiting from ICI due to PP should be explored further in larger prospective studies on real-life NSCLC patients undergoing ICI.