Introduction: Pulmonary embolism (PE) is a common cardiovascular condition with high mortality rates if left untreated. Given the non-specific and varied symptoms of PE, its diagnosis remains challenging and approaches can lend themselves to inefficiencies through over-testing and over-diagnosis. Clinicians rely on a multi-component and sequential approach, including clinical risk assessment, rule-out biomarkers, and diagnostic imaging. This study assessed the potential cost-effectiveness of different diagnostic algorithms. Methods: A cost-utility model was developed with an upfront decision tree capturing the diagnostic accuracy and a Markov cohort model reflecting the lifetime disease progression and clinical utility of each diagnostic strategy. 57 diagnostic strategies were evaluated that were permutations of various clinical risk assessment, rule-out biomarkers and diagnostic imaging modalities. Diagnostic test accuracy was informed by systematic reviews and meta-analyses, and costs (2016 CAD) were obtained from Canadian costing databases to reflect a health-care payer perspective. Separate scenario analyses were conducted on patients contra-indicated for computed tomography (CT) or who are pregnant as this entails a comparison of a different set of diagnostic strategies. Results: Six diagnostic strategies formed the efficiency frontier. Diagnosing patients with PE was generally cost-effective if willingness-to-pay was greater than $1,481 per quality-adjusted-life year (QALY). CT dominated other imaging modality given its greater diagnostic accuracy, lower rates of non-diagnostic findings and lowest overall costs. The use of clinical prediction rules to determine clinical pre-test probability of PE and the application of rule-out test for patients with low-to-moderate risk of PE may be cost-effective while reducing the proportion of patients requiring CT and lowering radiation exposure. At a willingness-to-pay of $50,000 per QALY, the strategy of Wells (2 tier) --> d-dimer --> CT --> CT was the most likely cost-effective diagnostic strategy. However, different diagnostic strategies were considered cost-effective for pregnant patients and those contra-indicated for CT. Conclusion: This study highlighted the value of economic modelling to inform judicious use of resources in achieving a diagnosis for PE. These findings, in conjunction with a recent health technology assessment, may help to inform clinical practice and guidelines. Which strategy would be considered cost-effective reflected ones willingness to trade-off between misdiagnosis and over-diagnosis.