Abstract Introduction Aim of this study is to determine whether quality of life (QoL) assessment in association with instrumental evaluation can help to identify factors predictive of outcome both in surgically and medically treated GERD patients. Methods Between January 2005 and June 2010, 301 patients affected with GERD were included in the study. QoL was evaluated by means of GERD-HRQL and SF-36 questionnaires administered before treatment, at 6 months, at 1 year follow-up and at the end of the study. The multivariate analysis was used to detect if variables such as sex, age, heartburn, acid regurgitation, dysphagia, presence of esophagitis, percentage of total time at pH < 4, symptom index score (SI), the SF-36 and HRQL scores before treatment, at 6 months and 1 year could affect the QoL questionnaires scores at the end of the study. Results One hundred forty-seven patients were included in the surgical group and 154 in the medical group. No differences with regard to gender, age, mean SF-36 and HRQL scores before treatment were documented. At the end of the study, quality of life was significantly improved for SF-36 and HRQL scores, either for surgical or medical group. The multivariate analysis showed no factors individually affected the SF-36 and the HRQL scores, but symptom index score (SI) and QoL questionnaires scores at 6 months and 1 year follow-up. Conclusions The combined use of pHmetry with evaluation of SI and QoL questionnaires can predict the outcome of GERD patients managed either by medical or surgical therapy.