AIMS: Reflux symptoms are highly prevalent and non-specific; hence, in the absence of alarm symptoms, endoscopy referral decisions are challenging. This study evaluated whether a non-endoscopic Cytosponge could detect benign oesophageal pathologies and thus have future potential in triaging patients with persistent symptoms. METHODS AND RESULTS: Two complementary cohorts were recruited: (i) patients with reflux symptoms and no prior endoscopy (n = 409), and (ii) patients with reflux symptoms referred for endoscopy (n = 411). All patients were investigated using the Cytosponge and endoscopy. Significant epithelial inflammation was present in 130 (16%) Cytosponge samples, 32 of which had ulcer slough. Candida and significant inflammation was detected in a further 22 (2.3%) cases; epithelial infiltration with >15 eosinophils/high-power field reflecting possible eosinophilic oesophagitis (EOE) in five (0.6%); and viral inclusions suggestive of herpes oesophagitis in one (0.1%). No significant pathology was detected in the majority, 662 (81%), of Cytosponge samples. Cytosponge and endoscopy findings were in agreement in 574 (70%) cases, in 165 (67%) of the discordant cases one investigation showed mild inflammation while the other was negative, with an additional 22 (8.9%) differing on the extent of inflammation. Eighteen cases with severe inflammation, six with candida and two with EOE were detected only at endoscopy, while 18 with candida and significant inflammation, 13 with ulcer slough, one probable EOE and one viral oesophagitis were identified on the Cytosponge only. CONCLUSIONS: The Cytosponge detects a range of benign oesophageal pathologies, and therefore has potential clinical utility in the triaging of patients with troublesome reflux symptoms. This warrants further investigation.