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Abstract A blood test identifying patients at increased risk of pulmonary hypertension (PH) could streamline the investigative pathway. The prospective, multicenter CIPHER study aimed to develop a microRNA‐based signature for detecting PH in breathless patients and enrolled adults with a high suspicion of PH who had undergone right heart catheterization (RHC). The CIPHER‐MRI study was added to assess the performance of this CIPHER signature in a population with low probability of having PH who underwent cardiac magnetic resonance imaging (cMRI) instead of RHC. The microRNA signature was developed using a penalized linear regression (LASSO) model. Data were modeled both with and without N‐terminal pro‐brain natriuretic peptide (NT‐proBNP). Signature performance was assessed against predefined thresholds (lower 98.7% CI bound of ≥0.73 for sensitivity and ≥0.53 for specificity, based on a meta‐analysis of echocardiographic data), using RHC as the true diagnosis. Overall, 926 CIPHER participants were screened and 888 were included in the analysis. Of 688 RHC‐confirmed PH cases, approximately 40% were already receiving PH treatment. Fifty microRNA (from 311 investigated) were algorithmically selected to be included in the signature. Sensitivity [97.5% CI] of the signature was 0.85 [0.80–0.89] for microRNA‐alone and 0.90 [0.86–0.93] for microRNA+NT‐proBNP, and the corresponding specificities were 0.33 [0.24–0.44] and 0.28 [0.20–0.39]. Of 80 CIPHER‐MRI participants with evaluable data, 7 were considered PH‐positive by cMRI whereas 52 were considered PH‐positive by the microRNA signature. Due to low specificity, the CIPHER miRNA‐based signature for PH (either with or without NT‐proBNP in model) did not meet the prespecified diagnostic threshold for the primary analysis.