Objective: To evaluate the cost-effectiveness of hepatic resection ("metastasectomy") in patients with metachronous liver metastases from colorectal carcinoma (CRC), and to investigate the impact of operative and follow-up strategies on outcomes, cost, and cost-effectiveness. Summary Background Data: There is substantial evidence that resection of CRC liver metastases can result in long-term survival in some patients. However, several unresolved issues are difficult to address using currently available clinical data. These include the appropriate threshold for resection, whether to perform repeat resection, and the relative cost-effectiveness of the procedure(s). Methods: The authors developed a state-transition Monte Carlo decision model to evaluate the (societal) cost-effectiveness of hepatic metastasectomy in patients with metachronous CRC liver metastases. The model tracks the presence, number, size, location, growth, detection, and removal of up to 15 individual metastases in each patient. Survival, quality of life, and cost are predicted on the basis of disease extent. Imaging and surgery affect outcomes via detection and removal of individual metastases. Several patient management strategies were developed and compared with respect to cost, effectiveness, and incremental cost-effectiveness ($/quality-adjusted life year [QALY]). A reference strategy in which metastasectomy is not offered and imaging is not performed for the purpose of assessing resectability or operative planning ("nosurgery" strategy) was included for comparison. Extensive sensitivity analysis was performed to evaluate the impact of alternative model assumptions on results. Results: A strategy permitting resection of up to six metastases and one repeat resection, with CT follow-up every 6 months, resulted in a, gain of 2.63 QALYs relative to the no-test/no-treat strategy, at an incremental cost of $13,100/QALY. When additional surgical strategies were considered, the incremental cost-effectiveness ratio (ICER; relative to the next least effective strategy) of the six metastases, one repeat, 6-month strategy was $31,700/QALY. Across a range of model assumptions, more aggressive treatment strategies (i.e., resection of more metastases, resection of recurrent metastases) were superior to less aggressive strategies and had ICERs below $35,000/QALY. Findings were insensitive to changes in most model parameters but somewhat sensitive to changes in surgery and treatment costs. Conclusions: Hepatic metastasectomy is a cost-effective option for selected patients with metachronous CRC metastases limited to the liver. When considering metastasectomy, more aggressive approaches are generally preferred to less aggressive approaches. Overall, surgeons should be encouraged to consider resection for all patients whose metastases can technically be removed.