Published evidence suggests that frequent hemodialysis (more than three times per week) for patients with ESRD may improve health-related quality of life and has the potential to increase longevity and reduce hospitalization and other complications. Here, a Monte Carlo simulation model was used to compare varying combinations of in-center hemodialysis frequency (three to six treatments per week) and session length (2 to 4.5 hours per session) with regard to unadjusted and quality-adjusted life-years and total lifetime costs for a cohort of 200,000 patients, representing the prevalent ESRD population. The incremental cost-effectiveness ratio was calculated for the various regimens relative to a conventional hemodialysis regimen (three treatments per week, 3.5 hours per session). Using conservative assumptions of the potential effects of more frequent hemodialysis on outcomes, most strategies achieved a cost-effectiveness ratio of <$125,000, although all had a cost-effectiveness ratio of >$75,000. The cost-effectiveness ratio increased with the frequency of hemodialysis. More frequent in-center hemodialysis strategies could become cost-neutral if the cost per hemodialysis session could be reduced by 32 percent to 43 percent. No other change in model assumptions achieved cost neutrality. In conclusion, given the extraordinarily high costs of the ESRD program, the viability of more frequent hemodialysis strategies depends on significant improvements in the economic model underlying the delivery of hemodialysis.