The effect of proton pump inhibitor (PPI) therapy on extraesophageal or atypical manifestations of gastroesophageal reflux disease (GERD) remains unclear. This study aimed to evaluate the prevalence of atypical manifestations in patients with acid reflux disease and the effect of PPI treatment. Patients with symptoms and signs suggestive of reflux were enrolled. Erosive esophagitis was stratified using the Los Angeles classification. Demographic data and symptoms were assessed using a questionnaire and included typical symptoms (heartburn, regurgitation, dysphagia, odynophagia), and atypical symptoms (e.g., chest pain, sialorrhea, hoarseness, globus sensation, chronic coughing, episodic bronchospasm, hiccup, eructations, laryngitis, and pharyngitis). Symptoms were reassessed after a 3-month course of b.i.d. PPI therapy. A total of 266 patients with a first diagnosis of GERD (erosive, 166; non-erosive, 100) were entered in the study. Presentation with atypical symptoms was approximately equal in those with erosive GERD and with non-erosive GERD, 72% vs 79% (P = 0.18). None of the study variables showed a significant association with the body mass index. PPI therapy resulted in complete symptom resolution in 69% (162/237) of the participants, 12% (28) had improved symptoms, and 20% (47) had minimal or no improvement. We conclude that atypical symptoms are frequent in patients with GERD. A trial of PPI therapy should be considered prior to referring these patients to specialists.