Little is known about prolonged effect of baclofen on oesophageal and lower oesophageal sphincter (LOS) motility. We aimed at investigating the oesophageal motility in gastro-oesophageal reflux disease (GORD) patients 24 h before and after the administration of multiple doses of baclofen. Twenty-one GORD patients underwent a 48-h manometry recording the swallows, the oesophageal and the LOS motility. During the second 24-h period, patients received baclofen 10 mg or placebo four times per day in a double-blind randomized fashion. Baclofen increased the LOS basal tone in comparison with baseline (P = 0.02), with a concomitant reduction in the number of transient LOS relaxations (TLOSRs) (P = 0.01). Moreover, baclofen induced a decrease of the swallows (P = 0.02) and of primary oesophageal body waves (P = 0.04) with no changes in the amplitude. Multiple doses of baclofen determine a reduction in the number of TLOSRs and an increase in the LOS tone throughout the 24 h. The concomitant decreased number of swallows and of primary peristalsis could depend on the well-known lower amount of reflux episodes induced by the drug. The potential therapeutic effect of baclofen could be expressed not only postprandially, but also in the fasting state when reflux episodes are present as well.