The treatment of colorectal cancer continues to pose major challenges for oncologists throughout the world. Uracil and tegafur (UFT), as an oral agent, represents a new patient-focused approach to managing a malignancy with few treatment alternatives other than an intravenous fluorouracil (5-FU)-based regimen. The ability of UFT to achieve equivalent clinical outcomes compared with continuous 5-FU infusion, along with its oral formulation and mild toxicity profile, provide a compelling backdrop for fiscal analysis. An economic assessment of therapy attributes and effects would, therefore, be prudent and necessary when deliberating the adoption of this chemotherapy regimen. We developed a pharmacoeconomic model in Brazil and Argentina identifying clinical practices associated with chemotherapy administration and adverse event management practices from a panel of physicians assembled in each country. Practice patterns and clinical events were then evaluated for resource utilisation trends. The perspective of this pharmacoeconomic analysis was that of the healthcare payor. Country-specific charge data were applied to the identified resources to arrive at an average cost per patient receiving a 6-cycle course of 5-FU with either levamisole and/or leucovorin as a modulator vs a modelled oral UFT/leucovorin regimen. As a comparator, the oral UFT/leucovorin regimen was modelled based on the expert panel's input. Adverse events and incidence data were derived from clinical trial data for both agents. Both agents were analysed in the treatment of metastatic disease and as adjuvant therapy. The principal findings of a cost-minimisation analysis in Brazil revealed approximately equivalent treatment costs for both regimens in the adjuvant setting. When analysing the metastatic treatment arm, costs diverged by $R335/per patient ($R = Reals - the currency of Brazil) in favour of a UFT regimen. The profile in Argentina yielded more dramatic differences, with a UFT regimen costing $P782/per patient ($P = Pesos - the currency of Argentina) less than a 5-FU regimen in the adjuvant setting. In the treatment of metastatic disease, a UFT regimen provided $P1188/per patient in savings over a 5-FU regimen. These differences are predominantly driven by the mild toxicity profile of UFT and its corresponding less severe adverse event management practice patterns. In addition, the oral formulation of UFT versus intravenous 5-FU provides for ease of administration, lowering the total cost of care as well as likely impacting on the patient's quality of life. The pharmacoeconomic results suggest that a UFT regimen is a useful and economical alternative to the standard 5-FU regimen in the treatment of colorectal cancer in Brazil and Argentina.