Background/aims: To investigate the presence of seronegative celiac disease in patients with isolated refractory dyspepsia and gastroesophageal reflux disease (GERD)-related complaints. Methods: This was a single-center, prospective study performed at a tertiary care referral hospital. Among 968 consecutive patients, 129 seronegative patients with tissue damage consistent with Marsh IIIa classification or above were included. The patients were divided into two groups: dyspepsia (n=78) and GERD (n=51). Biopsies were taken from the duodenum regardless of endoscopic appearance, and patients with Marsh IIIa or above damage were advised to consume a gluten-free diet. The Glasgow Dyspepsia Severity (GDS) score, Reflux Symptom Index (RSI), and Biagi score were calculated at baseline and every 3 months. Control endoscopy was performed every 6 months during follow-up. Results: The median follow-up time was 19.9 months (range, 6 to 24 months) in the dyspepsia group and 19.2 months (range, 6 to 24 months) in the GERD group. All the patients were positive for the HLA-DQ2 and DQ8 haplotypes. The differences between the mean GDS scores (14.3±2.1 vs 1.1±0.2, respectively, p<0.05), RSI scores (6.3±0.8 vs 0.7±0.1, respectively, p<0.05), and Biagi scores (3.1±0.4 vs 0.7±0.3 in the dyspepsia group and 2.5±0.4 vs 0.5±0.2 in GERD group) before and after implementation of the gluten-free diet were statistically significant. The decreases in the scores were consistent with improvements in the histological findings. There was no significant correlation between endoscopic appearance and histological examination results (p=0.487). Conclusions Seronegative celiac disease may be considered in this group of patients. Even if a patient is seronegative and has normal endoscopic findings, duodenal biopsy should be considered.