In Sjögren's syndrome (SS), oral dryness (xerostomia) is frequently the most bothersome symptom. An H2 histamine receptor antagonist is often administered to SS patients to treat associated superficial gastritis. The aim of the present study was to assess the ability of nizatidine, an H2 receptor antagonist, to also relieve xerostomia in patients with primary SS. Twenty-seven patients with primary SS were randomly assigned to receive nizatidine (n=14, 300 mg a day) or another H2 blocker, famotidine (n=13, 40 mg a day; control), were followed for eight weeks, and were asked for both subjective and objective assessments of oral dryness using a visual analog scale (VAS; 1-100 mm) and the Saxon's test, respectively. Patients receiving oral nizatidine, but not famotidine, obtained significant objective relief from their xerostomia (Saxon's test; baseline, 0.57 g/2 min; after eight weeks, 0.90 g/2 min, P<0.05). VAS scores indicated that nizatidine also provides mild improvement (20% improvement over baseline) of xerostomia-related clinical conditions, including mouth dryness and difficulty in chewing, tasting and swallowing food. Both drugs were generally well tolerated, without adverse effects. The present preliminary study suggests that nizatidine may represent a new option for the treatment of xerostomia in SS.