Atrial fibrillation (AF) is the most common arrhythmia and a major marker of stroke risk. Early detection is crucial and, once diagnosed, anticoagulation therapy can be initiated to reduce stroke risk. The aim of this study was to assess the cost-effectiveness of employing an insertable cardiac monitor (ICM), BIOMONITOR, for the detection of AF compared to standard of care (SoC) ECG and Holter monitoring in patients with cryptogenic stroke, that is, stroke of unknown origin and where paroxysmal, silent AF is suspected. A Markov model was developed which consisted of five main health states reflecting the potential lifetime evolution of the AF disease: post cryptogenic stroke (index event), subsequent mild, moderate and severe stroke, and death. Sub-states were included to track a patient's AF diagnostic status and the use of antiplatelet or anticoagulant therapy. AF detection was assumed to result in a treatment switch from aspirin to anticoagulants, except among those with a history of major bleeding. Detection yield and accuracy, clinical actions and treatment effects were derived from the literature and validated by an expert clinician. All relevant costs from a US Medicare perspective were included. An ICM-based strategy was associated with a reduction of 39 secondary ischemic strokes per 1000 patients monitored compared with SoC. Total per patient costs with an ICM were higher (US$90,052 vs. US$85,157) although stroke-related costs were reduced. The use of an ICM was associated with a base-case incremental cost-effectiveness ratio of US$18,487 per life-year gained compared with SoC and US$25,098 per quality-adjusted life year gained, below established willingness-to-pay thresholds. The conclusions were found to be robust over a range of input values. From a US Medicare perspective the use of a BIOMONITOR represents a cost-effective diagnostic strategy for patients with cryptogenic stroke and suspected AF.