OBJECTIVES: To estimate the potential cost effectiveness of maintenance therapy to prevent disease progression following chemotherapy for malignant mesothelioma (MM). METHODS: Decision analytic modeling was performed using a Markov cohort approach to estimate the incremental cost effectiveness of a post-chemotherapy maintenance therapy for MM, measured as cost per quality-adjusted life years gained.  The perspective of the payer was taken. Entering the model were 100 males, age 65 years, having non-progressed MM following completion of a standard regimen chemotherapy. Rate of progression and overall survival were derived from a phase III trial with pemetrexed plus cisplatin, and cycles were 1 month in length. Health utilities represented values used in similar studies, applied to patients with non-progressed and progressed MM health states. We assumed that the maintenance therapy would reduce the rate of disease progression by 25%.  As U.S. data regarding health care utilization among patients with MM is lacking, published cost estimates for lung cancer were applied. Outcomes and costs were discounted at 3.5% annually. Sensitivity analyses examined the robustness of the model when varying values were used for the costs of care and medication, and for treatment effectiveness. RESULTS: Following standard chemotherapy for MM, a maintenance therapy effective in reducing the rate of disease progression by 25% would yield an incremental cost effectiveness ratio (ICER) of $59,479/ quality-adjusted life years gained (QALY), compared with usual care. A 50% increase in the monthly cost of the maintenance therapy yielded an ICER of $85,336 / QALY, while decreasing the effectiveness from 25% to 12.5% yielded an ICER of $100,565 / QALY. CONCLUSIONS: Applications for maintenance therapy continue to expand in oncology, and in mesothelioma would represent a significant advancement in care, which could be cost-effective to U.S. payers.