Background/Rationale: between 10-40% of patients receiving fluoropyrimidine (FP) chemotherapies (capecitabine and 5-Fluorouracil) develop grade ≥ 3 toxicities, requiring hospitalisation, admission to intensive care and even resulting in death in 1% of patients. Upfront evaluation of the DPYD gene (encodes dihydropyrimidine dehydrogenase, the critical enzyme involved in 5FU metabolism) can identify patients at risk of severe toxicity and allow an opportunity for clinicians to adjust FP chemotherapy dosing prior to administration to reduce toxicities. This will in turn reduce the associated health economic burden of hospital-based management of FP induced toxicities. Methods: GeneScreen 5-FU is a national initiative focused on pharmacogenomic screening of the DPYD gene to allow personalised prescribing for patients embarking on FP chemotherapies. Upfront genotyping and genotype guided dose-adjustment is expected to lower the incidence of grade ≥ 3 toxicities and improve health economic impact, both of which will be assessed within the scope of this trial. Patient and clinician perspectives will be explored to encourage sustainable development of this pharmacogenomic initiative. We intend to genotype 5000 patients across Australia throughout the course of this project. We are conducting a small feasibility (n=200) of upfront UGT1A1 genotyping within the GeneScreen cohort. Impact: This large-scale collaborative trial involves approximately 30 clinical sites across Australia, including metropolitan, regional and telehealth sites. We have recruited almost 900 participants since initiation 6 months ago. This study is already demonstrating high through-put feasibility of DPYD pharmacogenomic screening and application of genotype-guided drug dosing to improve patient tolerance of chemotherapy. We await further recruitment to commence health economic impact evaluation. GeneScreen will serve as a prototype for the development and implementation of other pharmacogenomic programmes within Australia.