The objective of the study was to investigate the influence of anti-reflux medications on the management of periprosthetic leakage in laryngectomised patients with prosthetic voice rehabilitation. Sixty patients underwent laryngectomy and prosthetic voice rehabilitation. In a prospective non-randomised study, we examined the patients clinically and assessed the presence of reflux disease using 24-h dual-probe pH monitoring before and 6 months after oral anti-reflux treatment with proton pump inhibitors (PPIs). The severity of reflux, the effectiveness of anti-reflux therapy, and the clinical success of treatment were evaluated. Reflux parameters before and after anti-reflux therapy as well as the severity and incidence of periprosthetic leakage before and after PPI therapy were the main outcome measures. The absolute number of reflux events was 162.2 (+/-144.3) before treatment and 63.1 (+/-87.9) after treatment with PPIs (p = 0.031). The reflex area index score decreased from 327.1 (+/-419.3) without PPIs to 123.8 (+/-249.7) with PPIs (p = 0.0228). The mean DeMeester score was 108.3 (+/-85.4) before treatment and 47.4 (+/-61.7) after 6 months of treatment (p = 0.0557). The relative risk of periprosthetic leakage decreased to 0.5 after anti-reflux treatment. In 19 patients, leakage problems were successfully managed by rigorous treatment with PPIs. No further surgical procedures were required in these cases. Rigorous anti-reflux treatment leads to an improvement in parameters that can be assessed objectively by 24-h dual-probe pH monitoring. In the majority of patients, the symptoms associated with periprosthetic leakage can be improved or cured.