Background: Pharmacogenetics is the study of genetic variants that define drug metabolism and dosing requirements, response or toxicity. Knowledge regarding drug-drug interactions and individual variations in genes involved in drug metabolism is increasing. Since patients with cancer often take several drugs (polypharmacy), they have a higher risk of severe drug interactions. The FDA lists several pharmacogenetic biomarkers in drug labeling, including genetic variants that impact how certain medications are prescribed. The drugs listed span multiple medical applications, including but not limited to oncology, primary care, psychiatry, neurology, cardiology, and many more. Adverse drug reactions are a significant cause of morbidity and mortality, yet the use of pharmacogenetic testing has not yet become established as a routine in clinical practice. Herein we sought to study the feasibility of applied pharmacogenetics in a pilot drug safety program in patients with advanced cancer. Methods: We enrolled patients in a prospective single-center IRB approved study. Patients with advanced cancer on three or more drugs about to begin chemotherapy at the Hoag Family Cancer Institute were eligible. Informed consent was obtained from the study participants, and their samples were sent to a CLIA laboratory to conduct a 25-gene pharmacogenetics testing panel, which includes “major drug-metabolizing enzymes” CYP2D6, CYP2C19, CYP2C9, CYP3A4, and CYP3A5 as well as other genes with known drug implications. We recorded patients’ demographics and clinical information. In addition, participant’s drug lists were assessed for potential polypharmacy interactions. Results: We analyzed the results from 36 patients, 20 females and 16 males, enrolled between December 2017 and June 2020. Pharmacogenetics results from these patients showed that 61% (22 patients) had a variant with gene drug interaction indication. The most common variants were identified in the CYP2D6 gene, followed by CYP2C19, CYP3A4, and CYP3A5. Of these 22 patients, seven patients had at least one major criterion (drug interactions may lead to severe clinical effects), and eight patients with reported moderate criteria (may lead to substantial clinical effects). Additionally, seven patients had variants with both major and moderate criteria. Patients were taking an average of 10 medications per person ranging from 3-19 drugs. No patient, however, experienced significant drug toxicity during the observation interval. Conclusions: Patients with advanced cancer are at particular risk for polypharmacy and adverse drug reactions. Our data report supports pharmacogenetics testing as being feasible for oncology patients. Therefore, programs to prevent or limit the frequency and severity of drug reactions warrant further exploration as they offer the potential to improve patient safety and decrease healthcare costs.