Selection of the optimal procedure for minimally invasive diagnosis of peripheral pulmonary lesions (PPLs) may be based on clinical factors; however, selection of diagnostic strategy may also be influenced by cost. Economic analysis of minimally invasive diagnosis of PPL has not been performed previously. Decision-tree analysis was applied to compare downstream costs of endobronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB) with computed tomography-guided percutaneous needle biopsy (CT-PNB). Calculations were based on real costs derived from patient data. Sensitivity analyses and probabilistic sensitivity analysis were undertaken to identify the more cost-beneficial approach for varying input parameter values. Cost-effectiveness calculations were based on estimated disutility, according to the wait-trade-off technique. For base-case analysis, initial evaluation with CT-PNB was cost-beneficial (AU$2,724 versus EBUS-TBLB AU$2,748). The variable which exerted the most influence on cost-benefit outcomes was the cost of managing complications. CT-PNB remained the more cost-effective procedure at base-case parameters, although thresholds were identified during sensitivity analysis where EBUS-TBLB became more cost-effective. The costs of EBUS-TBLB and CT-PNB to evaluate PPL appear to be equivalent, but specific clinical-radiologic factors known to influence procedural outcomes will influence cost-benefit outcomes. Further evaluation of patient preferences and their influence on cost-effectiveness are required.