Gastroesophageal reflux (GER) is a common, chronic, relapsing symptom. Often people self-diagnose and self-treat it even though health-related quality of life is significantly impaired. In the lack of a valid alternative approach, current treatments focus on suppression of gastric acid secretion by the use of proton pump inhibitors (PPIs), but people with GER have a significantly lower response rate to therapy. We designed a randomized double-blinded controlled clinical study to evaluate the efficacy and the safety of a formulation based on sodium alginate/bicarbonate in combination with extracts obtained from Opuntia ficus-indica and Olea europaea associated with polyphenols (Mucosave®; verum), on GER-related symptoms. Male/female 118 (intention to treat) subjects with moderate GER and having at least 2 to 6 days of GER episodes/week were treated with verum (6 g/day) or placebo for two months. The questionnaires Gastroesophageal Reflux Disease-Health-Related Quality of Life (GERD-HRQoL) and Gastroesophageal Reflux Disease Symptom Assessment Scale (GSAS) were self-administered by participants before the treatment and at the end of the treatment. Verum produced statistically significant reduction of GERD-HRQoL and GSAS scores, -56.5% and -59.1%, respectively, in comparison to placebo. Heartburn and acid regurgitation episodes for week were significantly reduced by verum (p < 0.01). Results indicate that Mucosave formulation provides an effective and well-tolerated treatment for reducing the frequency and intensity of symptoms associated with gastroesophageal reflux.