Abstract: Objective To study the differences between gastroesophageal reflux disease (GERD) with atypical symptoms (a-GERD) and typical symptoms (t-GERD). Methods 30 patients of suspected a-GERD were recruited and examined with upper gastrointestinal endoscopy, high-resolution manometry (HRM), 24 h esophageal multichannel intra-luminal impedance monitoring with pH sensor (MII-pH) and proton pump inhibitor (PPI) trials. The results were compared with those of 33 cases of GERD with typical symptoms. Results Among the 30 patients of suspected GERD, 24 were confirmed with a-GERD. One third of those patients were over sixty-years old, significantly higher than those with typical GERD (P<0.05). No significant differences in prevalence of esophageal mucosa breakage and esophageal manometry readings were found between the two groups (P>0.05). The a-GERD patients had higher data readings in 24 h esophageal MCII-pH monitoring than the t-GERD patients (P<0.05). Supine type of GER and mixed reflux were predominately seen in the a-GERD patients, while upright type of GER was predominate seen in the t-GERD patients. The response rate of PPI in the a-GERD patients was significantly lower than that in the t-GERD patients when a course of standard dosage of PPI was given (45.8% vs. 78.8%, P<0.01). But there was no significant difference in PPI response between these two groups when a second course with double standard dosage of PPI combined with pro-motility agents were given (72.7% vs. 88.0%, P<0.05). Conclusion Compared with patients of t-GERD, older onset age, more severe degree of acid reflux are presented in patients of a-GERD. a-GERD should be considered when it is hard to explain the symptoms of upper part of the chest in clinical practice. 24 h esophageal MII-pH monitoring and/or diagnostic therapy with double standard dosage of PPI helps make a correct diagnosis.