Background: Over 26 million people suffer from heart failure (HF) globally. Current diagnosis of HF relies on clinical evaluation, blood assays and imaging techniques. Our aim is to develop a diagnostic assay to detect HF in at risk individuals within the community using human saliva as a medium, potentially leading to a simple, safe early warning system. Methods: Saliva samples were collected from healthy controls (n=36) and HF patients (n=75). Salivary proteome profiles were analysed by Sequential Window Acquisition of All Theoretical fragment ion spectra - Mass Spectrometry (SWATH-MS). A total of 738 proteins were quantified and 177 proteins demonstrated significant differences between HF patients and healthy controls. Candidate biomarkers were chosen based on their abundance and difference between the two cohorts. A multi-protein panel was developed using logistic regression analysis. The diagnostic performance of the multi-protein panel was assessed using receiver operative characteristic curves. The candidate proteins were further confirmed, using western blot analysis, and validated technically, using an independent biological cohort. Results: A group of six proteins were chosen in the discovery phase as potential candidates based on their differences in the abundance between the two cohorts. During the validation phase, two of the proteins were not detected with western blotting and as such were removed. The final panel consists of four proteins with sensitivity of 83.3%, specificity of 62.5% with an area under ROC curve of 0.78 in discriminating healthy controls from NYHA class I/II HF patients, and was validated in a second independent cohort study. Conclusion: Analysis of salivary proteome using SWATH-MS revealed novel HF-specific protein candidates yielding high diagnostic performance. A multi-centre longitudinal clinical trial will be the next step before clinical implementation of this panel.