Background: 5-FU has been 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 PK-guided dosing of 5-FU improves clinical efficacy with reduced toxicity. We conducted this Quality Improvement project 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 at the UPMC Cancer Center who underwent PK-guided optimization of 5-FU dosing using an immunoassay (OnDose or MyCare) were included in the analysis. Results: A total of 21 patients (8 males, 13 females) meeting the entry criteria have been identified to date. The median age was 61 years (range, 41-82). Six patients had stage III disease, and the remaining 15 patients had stage IV disease. The 5-FU infusional regimens included FOLFOX6 (N=18) and FOLFIRI (N=3). A total of 49 5-FU PK tests were performed for these 21 patients. The median number of tests performed per patient was 2 (range, 1-4). On initial testing, only 19% (N=4) patients had 5-FU systemic exposure, measured as an area under the curve (AUC), within the suggested target range of 20-30 mg^.hr/L (67% (N=14) patients were below while 14% (N=3) patients were above the target range). Of the 14 patients below the target range on initial testing, 5-FU doses were increased in 11 patients for the subsequent treatment cycle. The median number of dose modifications required to achieve the target PK levels in these patients was 1 (range, 1-2). The majority of these patients (82%, N=9) tolerated the increased 5-FU dose well without worsening of 5-FU related toxicity. Conclusions: Our data shows that 5-FU dosing based on BSA results in sub-optimal 5-FU exposure levels for the majority of patients (81%). PK-guided dose adjustment of 5-FU appears to be a practical and feasible approach to personalize optimal 5-FU exposure with potential for application in routine clinical practice.