OBJECTIVES: Present the economic study design of the OPTIMIZE study on orbital atherectomy system (OAS) and drug-coated balloon (DCB) treatment of peripheral artery disease (PAD) patients. Treating patients with calcified peripheral arterial lesions can be challenging and costly. The impact of OAS and DCBs in treating calcified lesions has been studied independently. The objective of this study design is to assess the economic impact of treating below-the-knee (BTK) calcified PAD lesions with OAS+DCB compared to treating BTK calcified lesions with DCB alone (without OAS). METHODS: This prospective, multi-center, post-market pilot study comparing OAS with adjunctive DCB angioplasty versus DCB angioplasty alone for treatment of calcified BTK lesions is a 1:1 randomized controlled study of 50 patients with calcification. In addition to clinical outcomes, health economic outcomes will be collected for the index procedure as well as additional procedures required during the clinical follow-up period. RESULTS: Health economic outcomes will be measured at the index procedure, at 30 days, 3 months, 6 months, 12 months, and 24 months post procedure for the treatment of PAD and its complications (repeat procedures, amputations, etc.). Health-related quality of life will be measured using the EQ-5D instrument. Resource utilization will be collected from case report forms and hospital accounting systems, using site-specific procedure code information of relevant OPS (German sites), CHOP (Swiss sites), and MEL codes (Austrian sites). Analyses from the third-party payer perspective will be informed by country-specific reimbursement amounts, using Germany as the initial reference case. Resulting cost difference and incremental cost-effectiveness are the main economic outcomes targeted in this analysis.   CONCLUSIONS: Prospective inclusion of health-economic endpoints in clinical trials for PAD is important to support future decision-making by payers and providers. The OPTIMIZE study collects targeted information on quality of life and resource utilization to facilitate future health-economic analyses.