Background: 5-FU continues to serve as the backbone of systemic combination chemotherapy for treatment of CRC in the adjuvant and metastatic disease settings. The dosing of 5-FU has traditionally been based on body surface area (BSA). Growing evidence suggests that BSA-based 5-FU dosing has several limitations, and that pharmacokinetic (PK)-guided dosing of 5-FU improves clinical efficacy with reduced toxicity. We conducted a QI study to evaluate the clinical feasibility of PK-guided 5-FU dose adjustment and its impact on clinical outcome. Methods: CRC patients treated with combination chemotherapy regimens containing infusional 5-FU who underwent PK-guided optimization of 5-FU dosing using an antibody-based immunoassay (OnDose or MyCare) were included in the analysis. Results: A total of 58 patients (34 males, 24 females) meeting the entry criteria have been identified to date. The median age was 61 years (range, 27-85). Fifteen patients had stage III disease, and the remaining 43 patients had stage IV disease. The 5-FU infusional regimens included mFOLFOX6 (n=45) and FOLFIRI (n=13). A total of 143 5-FU PK tests were performed for these 58 patients. The median number of tests performed per patient was 2 (range, 1-5). On initial testing, only 36% (n=21) patients had 5-FU systemic exposure, measured as area under the curve (AUC), within the suggested target range of 20-30 mg^.hr/L. Fifty-five percent of the patients were below the target AUC while 9% (n=5) patients were above the target range. Of the 32 patients below the target range on 5-FU AUC test, the 5-FU doses were increased in 22 patients for the subsequent treatment cycle. The median number of dose modifications required to achieve the target AUC levels in these patients was 1 (range, 1-2). The majority of these patients (86%, n=19) tolerated the increased 5-FU dose well without worsening of 5-FU related toxicity. Conclusions: Our data provides further evidence that 5-FU dosing based on BSA results in sub-optimal 5-FU exposure levels for the majority of patients (64%). PK-guided dose adjustment of 5-FU appears to be a practical and feasible approach that can be applied in routine clinical practice.