OBJECTIVES: CALGB conducted a randomized trial to compare the survival duration, quality of life, and costs of hepatic artery infusion (HAI) versus systemic chemotherapy (SYS) as initial treatment for patients with colorectal cancer metastatic to the liver. We evaluated the lifetime incremental cost and benefit from a third-party payer perspective alongside that trial. METHODS: Resource use data were collected for all study patients through 18 months, regardless of disease progression, and a subset was followed until death. Unit costs were derived from itemized patient bills, adjusted using department-specific ratios of costs to charges. Utility weights were collected serially from trial patients and used to calculate quality-adjusted survival. RESULTS: During the first 18 months, inpatient stays accounted for the highest proportion of overall costs (47%) in the HAI arm, while outpatient visits were the major component of costs (40%) in the SYS arm. In both arms, non-protocol chemotherapy treatment given after progression accounted for approximately half of all outpatient care costs. Compared to systemic 5-fluorouracil and leucovorin, hepatic artery infusion of floxuridine increased quality-adjusted survival by 0.46 quality-adjusted life years, at an incremental cost of $50,867. Most of the difference in costs occurred early, and was attributable to higher inpatient care and surgery costs. The incremental cost-effectiveness ratio (ICER) was $112,924 per quality-adjusted life year. The bootstrap-derived distribution of ICER was quite precise, with only 28% and 90% of simulations falling under $100,000/QALY and $200,000/QALY, respectively. The magnitude of the ICER was robust in sensitivity analyses. CONCLUSIONS: Hepatic artery infusion for metastatic colorectal cancer resulted in a substantial increase in quality-adjusted survival at an ICER that compares favorably with other widely used cancer treatments in the United States. These results create a benchmark against which the costs and cost-effectiveness of new agents can and should be evaluated.