Background: DPYD gene encodes DPD, the rate-limiting enzyme responsible for catabolism of 5-FU and is responsible for > 85% of 5-FU elimination. Deficiency of DPD due to DPYD polymorphism gives rise to severe 5-FU AEs from reduced catabolism. This pharmacogenetic ‘DPD syndrome’ manifests typically as severe or fatal diarrhea, mucositis/stomatitis, myelosuppression and even rare toxicities, such as hepatitis, encephalopathy and acute cardiac ischemia following first or second dose of 5-FU. The most compelling reason to introduce routine DPD testing is to avoid severe AEs in pts who receive 5-FU/CAP. DPYD mutations are found in 50% of severe 5-FU toxicity cases. Methods: We analyzed all pts who were tested for DPD deficiency after excessive toxicities from 5-FU/CAP, treated for GI cancers. DPD activity was evaluated by PBMC radioassay, genotyping of DPYD, or 2-¹³C uracil breath test after an informed consent. Demographics of pts, grades of toxicity, chemotherapy (dose, route) and outcomes were analyzed. Results: A total of 52 pts with DPD deficiency were identified [age range: 35 - 79 yrs; M:F = 1.3:1; Ethnicities: Caucasian (≥ 60%), African-American, unknown, Asian]. Most commonly used regimens in decreasing order were infusion 5-FU, CAP and bolus. Excessive AEs included mucositis (70%), diarrhea (40%), cytopenias (40%), nausea/vomiting (30%), HFS or skin rashes (20%), neurotoxicity (12%) and cardiotoxicity (5%). 11/12 pts had low DPD activity (range:0.064 – 0.18nmol/min/mg). DPYD genotyping showed: IVS14 + 1 G > A (c.1905+1 G > A, rs3918290) 38%, D949V (c.2846A > T, rs67376798) 21%, C29R (rs1801265) 4%, and Y186C (rs115232898, c.557 A > G) 2%. UraBT confirmed DPD deficiency in 2 pts: DOB₅₀ of 49.4% and 52.5%. Re-challenge with CAP in 5 pts resulted in atypical or similar AE. 6 pts received vistogard; 5 recovered. 3 pts died due to AEs. Conclusions:DPYD genotyping (+ TYMS) may identify ≥ 50% of pts, who are at greatest risk of AEs. At present, no formal recommendations regarding testing for DPYD exist except warning on FDA website and prescription inserts. Our data mandates the need for prospective studies to develop guidelines in pts receiving 5-FU/CAP.